Substituted imidazoles

ABSTRACT

The present invention relates to novel substituted imidazoles, to the use of these compounds as medicaments, to pharmaceutical compositions comprising the compounds, and to a method of treatment employing these compounds and compositions. The present compounds show a high and selective binding affinity to the histamine H3 receptor indicating a histamine H3 receptor antagonistic or agonistic activity. As a result, the compounds are useful for the treatment of disorders related to the histamine H3 receptor. More particularly, the present compounds possess a histamine H3 receptor agonistic activity and are accordingly useful in the treatment of disorders in which a histamine H3 receptor activation is beneficial.

RELATED APPLICATIONS

[0001] Benefit of U.S. Provisional Application Serial No. 60/334,209,filed on Nov. 29, 2001 is hereby claimed, and said application is hereinincorporated by reference in its entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to novel substituted imidazoles, tothe use of these compounds as medicaments, to pharmaceuticalcompositions comprising the compounds, and to a method of treatmentemploying these compounds and compositions. The present compounds show ahigh and selective binding affinity to the histamine H3 receptorindicating a histamine H3 receptor antagonistic or agonistic activity.As a result, the compounds are useful for the treatment of disordersrelated to the histamine H3 receptor. More particularly, the presentcompounds possess a histamine H3 receptor agonistic activity and areaccordingly useful in the treatment of disorders in which a histamine H3receptor activation is beneficial.

BACKGROUND OF THE INVENTION

[0003] The existence of the histamine H3 receptor has been known forseveral years and of current interest for the development of newmedicaments (see e.g. Stark, H.; Schlicker, E.; Schunack, W., Drugs Fut.1996, 21, 507-520; Leurs, R.; Timmerman, H.; Vollinga, R. C., Progressin Drug Research 1995, 45, 107-165). Recently, the histamine H3 receptorhas been cloned, cf. Lovenberg, T. W. et al, Molecular Pharmacology,June 1999, 55, 1101-1107. The histamine H3 receptor is a presynapticautoreceptor located in both the central and the peripheral nervoussystem, the skin and in organs such as the lung, the intestine, probablythe spleen and the gastrointestinal tract. The histamine H3 receptor hasbeen demonstrated to regulate the release of histamine and also of otherneurotransmitters such as serotonin and acetylcholine. Accordingly, thehistamine H3 receptor is an important target for new therapeutics.

[0004] H3 agonists can inhibit the release of calcitonin-gene-relatedpeptid (CGRP) from sensory C fibres (M. Imamura, Circ. Res., 78, 1996,863-869). Thus H3 agonists are especially useful for the treatment andprevention of diseases related to elevated CGRP levels and for thetreatment and prevention of inflammatory diseases, such as ischemicarrhythmias (Silver, R. B. et al., Proc. Natl. Acad. Sci. U.S.A., 98(5),2001, 2855-2859), myocardial ischemia and infarction (Expert Opin.Invest. Drugs (2000), 9(11), 2537-2542), migraine and asthma (Curr.Opin. Invest. Drugs (2000), 1(1), 86-89).

[0005] Furthermore H3 agonists have been reported to be of therapeuticuse in dyskinesia (WO 0130346), chronic vasomotor rhinitis and asanalgesics (Bulg. Chem. Commun. (2001), 33(1), 119-125/A. Rouleau,Pharmacol. Exp. Ther. (2000), 295(1), 219-225) or as gastroprotectivedrugs (G. Bertaccini, Dig. Dis. Sci., 40, 1995, 2052-2063).

[0006] Known H3 agonists, such as R-alpha-methylhistamine are frequentlypositively charged under physiological conditions (e.g. EP 0420396 A2).This property limits the use of such compounds as oral available drugsand has to be overcome for therapeutic purposes by e.g. anadministration, as a prodrug. The H3 agonists being subject of thispatent, are void of basic aliphatic amines and of positive charges underphysiological conditions and are superior compared to known H3 agonistsin this respect.

[0007] Furthermore a multitude of H3 ligands, e.g. the agonistthioperamide (Br. J. Pharmacol. (1996), 118(8), 2045-2052) or theagonist histamine (Semin. Cancer Biol. (2000), 10(1), 47-53) interactwith P450 isoenzymes implicating the problem of drug interactions upontherapeutic use. The H3 agonists being subject of this invention showsignificantly reduced interactions with P450 isoenzymes and aretherefore superior compared to known H3 agonists, too.

[0008] Imidazoles similar to the compounds of the present invention havepreviously been prepared, and their biological properties have beeninvestigated. Thus, WO 93/14070 and WO 96/29315 relates tomonosubstituted imidazole derivatives and their use as H3 receptorantagonists.Ciproxyfan and Iodoproxyfan, imidazole derivatives describedin this context, have been characterized as potent histamine H3 receptorantagonists by X. Ligneau et al. (J. Pharm. And Exp. Therapeutics, 287,1998, 658-666 and J. Pharmacol. Exp. Ther. (1994), 271(1), 452-9respectively).

[0009] Imidazoles containing substituents bearing a sulfonamidefunctionality have been described in WO 97/29092, WO 99/05115,imidazoles containing substituents bearing a sulfonamide functionalityor a sulfon linker have been described in WO 99/05114 and imidazolescontaining substituents bearing sulfonurea linkers have been describedin WO99/05141. Examples amongst these compounds have been described ashistamine H3 receptor ligands and more specifically as histamine H3receptor antagonists.

[0010] Imidazoles, being linked to a piperidine ring via one of thepiperidines carbon atoms, have been subject of EP 0 197 840 and of EP 0494 010. Amongst them GT2016 has been characterized in detail as anhistamine H3 receptor antagonist by C. E. Tedford et al. (J. Pharmacol.Exp. Ther. (1995), 275(2), 598-604).

[0011] Several publications disclose the preparation and use ofhistamine H3 agonists and antagonists. Thus, U.S. Pat. No. 4,767,778(corresponding to EP 214 058), EP 338 939, EP 0 339 208, EP 0 387 431,EP 531 219, EP 458 661, EP 0 680 960, EP 0 717 037, WO 91/17146, WO93/12108, WO 93/12107, WO 93/12093, WO 93/20061, U.S. Pat. No. 5,578,616(corresponding to WO95/14007), WO 94/17058, WO 96/38142, WO 96/38141, WO95/11894, WO 95/14007, WO 93/20061, WO96/40126, WO95/06037, WO 92/15567,WO 99/24405, WO 99/24406, WO 99/24421, WO 99/31089, WO 99/06377, U.S.Pat. No. 5,652,258, U.S. Pat. No. 5,837,718 and WO 94/17058 discloseimidazole derivatives having histamine H3 receptor agonistic orantagonistic activity.

[0012] Histamine receptor H3 agonists have been disclosed in EP 0 420396, EP 0 214 058, EP 0 338 939, JP06345642 and WO 91/17146.

[0013] However, the structures of the above summarized imidazolederivatives are quite different from that of the present compounds.Thus, none of the imidazole derivatives disclosed in these publicationshave a second substituent at position 5 of the imidazol group such as isthe case in the present compounds.

[0014] In view of the art's interest in histamine H3 receptor ligands,namely agonists and antagonists, novel compounds which interact with thehistamine H3 receptor would be a highly desirable contribution to theart. The present invention provides such a contribution to the art beingbased on the finding that a specific class of substituted imidazolecompounds displays a high and specific agonism at the histamine H3receptor.

DETAILED DESCRIPTION OF THE INVENTION

[0015] The present invention relates to novel, substituted imidazoles ofgeneral formula

[0016] wherein

[0017] R¹ is a hydrogen atom or a functional group which can beconverted into a hydrogen atom in vivo,

[0018] R² is a C₁₋₆-alkyl, C₃₋₇-cycloalkyl, aryl or aryl-C₁₋₂-alkylgroup,

[0019] n is 2, 3, 4 or 5,

[0020] X is an oxygen or sulfur atom or a —CO—, —O—CH₂- or —SO—CH₂-group,

[0021] Ar is a phenylene or naphthylene group,

[0022] a 5-membered heteroarylene group linked via a carbon or nitrogenatom containing

[0023] an imino group optionally substituted by an C₁₋₄-alkyl orC₁₋₄-alkyl-carbonyl group, an oxygen or sulfur atom,

[0024] an imino group optionally substituted by an C₁₋₄-alkyl group oran oxygen or sulfur atom and additionally a nitrogen atom,

[0025] an imino group optionally substituted by an C₁₋₄-alkyl group andtwo nitrogen atoms or

[0026] an oxygen or sulfur atom and two nitrogen atoms,

[0027] or a 6-membered heteroarylene group containing one or twonitrogen atoms,

[0028] while the above-mentioned phenylene or 5- or 6-memberedheteroarylene groups are optionally condensed via pairs of two adjacentcarbon atoms with one or two saturated, unsaturated or aromaticcarbocyclic or heterocyclic groups, which are optionally substituted byone or two carbonyl or C₁₋₃-alkyl groups,

[0029] and the resulting condensed bi- or tricycles may be linked to Xvia the carbocyclic or heterocyclic moiety, and

[0030] Y is a hydrogen, fluorine, chlorine, bromine or iodine atom, ahydroxy, cyano, C₁₋₆-alkyl, C₃₋₇-cycloalkyl, acetylene,C₁₋₄-alkyl-acetylene, C₁₋₄-alkyl-carbonyl, C₃₋₇-cycloalkyl-carbonyl,—C(═N—OH)—CH₃, phenyl, 5- or 6-membered heteroaryl, C₁₋₆-alkyloxy orphenyloxy group,

[0031] whilst the phenyl rings contained in all the above definitionsmay additionally be substituted by one or two fluorine, chlorine,bromine or iodine atoms, or by one or two C₁₋₆-alkyl or C₁₋₆-alkoxygroups, while the substituents may be the same or different, and

[0032] the hydrogen atoms of alkyl groups contained in the abovedefinitions may be partly or fully replaced by fluorine atoms,

[0033] and the diastereomers, enantiomers, mixtures and salts thereof,particularly the pharmaceutically acceptable salts thereof.

[0034] The compounds of general formula I, wherein Ar is a bond orwherein Y is one of the above-mentioned alkylsulfonyl, tosyl of silanylgroups, are usefull intermediates for the preparation of thepharmaceutically active compounds of general formula I.

[0035] The above definition of R¹includes a functional group which canbe converted into a hydrogen atom in vivo. This functional is in fact aprodrug group of the imino group. Such groups are for instance describedin WO 98/46576 and by N. M. Nielsen et al. in the International Journalof Pharmaceutics 1987, 39, 75 to 85.

[0036] Examples for a group cleavable in vivo to form a imino group,i.e. a prodrug group of the imino group, are a hydroxy group, a tritylgroup, an acyl group like a phenylcarbonyl group optionally mono- ordisubstituted by fluorine, chlorine, bromine or iodine atoms, by C₁₋₃alkyl or C₁₋₃ alkoxy groups, while the substituents may be the same ordifferent, a pyridinoyl group or an C₁₋₁₆ alkynoyl group like theformyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, a3,3,3-trichloropropionyl or allyloxycarbonyl group, a C₁₋₁₆alkoxycarbonyl or C₁₋₁₆ alkylcarbonyloxy group wherein the hydrogenatoms may be all or partly replaced by fluorine or chlorine atoms, likethe methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, tert.-butoxycarbonyl,pentoxycarbonyl, hexoxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl,decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl,hexadecyloxycarbonyl, methylcarbonyloxy, ethylcarbonyloxy,2,2,2-trichloroethylcarbonyloxy, propylcarbonyloxy,isopropylcarbonyloxy, butylcarbonyloxy, tert.-butylcarbonyloxy,pentylcarbonyloxy, hexylcarbonyloxy, octylcarbonyloxy, nonylcarbonyloxy,decylcarbonyloxy, undecylcarbonyloxy, dodecylcarbonyloxy orhexadecylcarbonyloxy group, a phenyl-C₁₋₆-alkoxycarbonyl group like thebenzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group,a 3-amino-propionyl group, in which the amino group is optionally mono-or disubstituted by C₁₋₆ alkyl or C₃₋₇ cycloalkyl groups, while thesubstituents may be the same or different, anC₁₋₃-alkylsulfonyl-C₂₋₄-alkoxycarbonyl,C₁₋₃-alkoxy-C₂₋₄-alkoxy-C₂₋₄-alkoxycarbonyl,R_(p)-CO—O—(R_(q)CR_(r))-O—CO—, C₁₋₆-alkyl-CO—NH-(R_(s)CR_(t))-O—CO— orC₁₋₆-alkyl-O—CO-(R_(s)CR_(t))-(R_(s)CR_(t))-O—CO- group, wherein

[0037] R_(p) is a C₁₋₈ alkyl, C₅₋₇ cycloalkyl, C₁₋₈ alkyloxy, C₅₋₇cycloalkyloxy, phenyl or phenyl-C₁₋₃-alkyl group,

[0038] R_(q) is a hydrogen atom, a C₁₋₃ alkyl, C₅₋₇ cycloalkyl or phenylgroup,

[0039] R_(r) is a hydrogen atom or a C₁₋₃ alkyl group and

[0040] R_(s) and R_(t), which may be the same or different, are each ahydrogen atom or a C₁₋₃ alkyl group.

[0041] Alkyl and alkoxy groups mentioned in the definitions above andbelow include straight-chained and branched alkyl groups, such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.-butyl,methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or tert.-butoxy groups.The hydrogen atoms of alkyl or alkoxy groups are optionally partly orfully replaced by fluorine atoms, like in the trifluormethyl ortrifluormethoxy group.

[0042] Cycloalkyl groups are defined as cyclic alkyl groups. Examplesfor cycloalkyl groups are the cyclopropyl, cyclobutyl, cyclopentanyl,cyclohexanyl and cycloheptanyl group.

[0043] An aryl group means, alone or in combination with other groups, aphenyl or naphthyl group optionally mono-, di- or trisubstituted byfluorine, chlorine, bromine or iodine atoms or C₁₋₄ alkyl or C₁₋₃ alkoxygroups, while the substituents may be the same or different.

[0044] A 5-membered heteroaryl group is a 5-membered aromatic groupcontaining

[0045] an imino group optionally substituted by an C₁₋₄-alkyl orC₁₋₄-alkyl-carbonyl group, an oxygen or sulfur atom,

[0046] an imino group optionally substituted by an C₁₋₄-alkyl group oran oxygen or sulfur atom and additionally a nitrogen atom,

[0047] an imino group optionally substituted by an C₁₋₄-alkyl group andtwo nitrogen atoms or

[0048] an oxygen or sulfur atom and two nitrogen atoms.

[0049] According to the invention, a 6-membered heteroaryl group is a6-membered aromatic group containing one or two nitrogen atoms.

[0050] A preferred embodiment according to the invention concernscompounds of general formula I, wherein

[0051] R¹ is a hydrogen atom or a trityl group,

[0052] R² is a C₁₋₄-alkyl, C₃₋₅-cycloalkyl or aryl group,

[0053] n is 2, 3 or 4,

[0054] X is an oxygen or sulfur atom or a —O—CH₂- or —SO—CH₂- group,

[0055] Ar is a 1,2-phenylene, 1,3-phenylene, 1,4-phenylene,2,5-naphthylene or 2,6-naphthylene group,

[0056] a 5-membered heteroarylene group linked via a carbon or nitrogenatom and a carbon atom containing

[0057] an imino group optionally substituted by an C₁₋₄-alkyl orC₁₋₄-alkyl-carbonyl group, an oxygen or sulfur atom,

[0058] an imino group optionally substituted by an C₁₋₄-alkyl group oran oxygen or sulfur atom and additionally a nitrogen atom,

[0059] an imino group optionally substituted by an C₁₋₄-alkyl group andtwo nitrogen atoms or

[0060] an oxygen or sulfur atom and two nitrogen atoms,

[0061] or a 6-membered heteroarylene group containing one or twonitrogen atoms,

[0062] while two adjacent carbon atoms of the above-mentioned phenyleneor 5- or 6-membered heteroarylene groups are optionally bridged by a—CH₂—CH₂—CH₂—CH₂—, -(C═O)-CH₂—CH₂—CH₂—, —C(CH₃)₂-CH₂—CH₂—C(CH₃)₂—,—CH═CH—CH═N—, —O—CH₂—O— or —N═CH—S- group

[0063] and the resulting bicycles are linked to X via the carbocyclicmoiety, and

[0064] Y is a hydrogen, fluorine, chlorine, bromine or iodine atom, ahydroxy, cyano, C₁₋₄-alkyl, C₃₋₅-cycloalkyl, acetylene,C₁₋₄-alkyl-acetylene, C₁₋₄-alkyl-carbonyl, C₃₋₅-cycloalkyl-carbonyl,phenyl, —C(═N—OH)-CH₃, C₁₋₆-alkyloxy, phenyloxy group or a 5- or6-membered heteroaryl group as defined above,

[0065] whilst the phenyl rings contained in all the above definitionsmay additionally be substituted by one or two halogen atoms, C₁₋₆-alkylor C₁₋₆-alkoxy groups while the substituents may be the same ordifferent and

[0066] the hydrogen atoms of alkyl groups contained in the abovedefinitions may be partly or fully replaced by fluorine atoms,

[0067] and the diastereomers, enantiomers, mixtures and salts thereof,particularly the pharmaceutically acceptable salts thereof,

[0068] particularly those compounds, wherein X is an oxygen or sulfuratom or a —O—CH₂- group.

[0069] Another preferred embodiment of the invention concerns compoundsof general formula I, wherein

[0070] R¹ is a hydrogen atom,

[0071] R² is a C₁₋₄-alkyl, C₃₋₅-cycloalkyl or phenyl group,

[0072] n is 2, 3 or 4,

[0073] X is an oxygen atom or a —O—CH₂- group,

[0074] Ar is a group selected from the formulae

[0075] Y is a hydrogen, fluorine, chlorine, bromine or iodine atom, ahydroxy, cyano, C₁₋₄-alkyl, C₃₋₅-cycloalkyl, acetylene,C₁₋₄-alkyl-carbonyl, C₃₋₅-cycloalkyl-carbonyl, phenyl, —C(═N—OH)-CH₃,C₁₋₃-alkoxy, phenyloxy or imidazolyl group,

[0076] whilst the phenyl rings contained in all the above definitionsmay additionally be substituted by a halogen atom, a C₁₋₃-alkyl orC₁₋₃-alkoxy group and

[0077] the hydrogen atoms of alkyl groups contained in the abovedefinitions may be partly or fully replaced by fluorine atoms,

[0078] and the diastereomers, enantiomers, mixtures, prodrugs and saltsthereof, particularly the pharmaceutically acceptable salts thereof.

[0079] Still another preferred embodiment of the invention concernscompounds of general formula I, wherein

[0080] R¹ is a hydrogen atom,

[0081] R² is a methyl, ethyl or isopropyl group,

[0082] n is 2, 3 or 4,

[0083] X is an oxygen atom or a —O—CH₂- group,

[0084] Ar is a 1,3- or 1,4-phenylene or 2,5-napthylene group and

[0085] Y is a hydrogen, fluorine, chlorine, bromine or iodine atom, ahydroxy, cyano, C₁₋₄-alkyl, acetylene, C₁₋₄-alkyl-carbonyl,C₃₋₅-cycloalkyl-carbonyl, phenyl, C₁₋₃-alkoxy, phenoxy or imidazolylgroup,

[0086] whilst the phenyl rings contained in all the above definitionsmay additionally be substituted by a fluorine, chlorine, bromine oriodine atom atom, a C₁₋₃-alkyl or C₁₋₃-alkoxy group and

[0087] the hydrogen atoms of alkyl groups contained in the abovedefinitions may be partly or fully replaced by fluorine atoms,

[0088] and the diastereomers, enantiomers, mixtures, prodrugs and saltsthereof, particularly the pharmaceutically acceptable salts thereof,most particularly those compounds, wherein

[0089] R² is a methyl group

[0090] and the diastereomers, enantiomers, mixtures, prodrugs and saltsthereof, particularly the pharmaceutically acceptable salts thereof.

[0091] Preferred compounds of general formula I are selected from thegroup consisting of

[0092] (a) 5-Methyl-4-[4-(naphthalen-2-yloxy)-butyl]-1H-imidazole,

[0093] (b) 4-[3-(4-Iodo-benzyloxy)-propyl]-5-methyl-1H-imidazole,

[0094] (c)5-Methyl-4-[3-(4-trifluoromethoxy-benzyloxy)-propyl]-1H-imidazole,

[0095] (d) 5-Methyl-4-[3-(naphthalen-2-ylmethoxy)-propyl]-1H-imidazole,

[0096] (e)5-Methyl-4-[3-(4-trifluoromethyl-benzyloxy)-propyl]-1H-imidazole,

[0097] (f) 4-[3-(3,5-Dichloro-benzyloxy)-propyl]-5-methyl-1H-imidazole,

[0098] (g)4-[3-(3,5-Bis-trifluoromethyl-benzyloxy)-propyl]-5-methyl-1H-imidazole,

[0099] (h) 4-[3-(3-Iodo-benzyloxy)-propyl]-5-methyl-1H-imidazole,

[0100] (i)5-Methyl-4-[3-(3-trifluoromethyl-benzyloxy)-propyl]-1H-imidazole,

[0101] (j) 4-[2-(4-Iodo-benzyloxy)-ethyl]-5-methyl-1H-imidazole,

[0102] (k)5-Methyl-4-[4-(4-trifluoromethoxy-benzyloxy)-butyl]-1H-imidazole and

[0103] (l) 4-[3-(3,5-Dimethyl-benzyloxy)-propyl]-5-methyl-1H-imidazole,

[0104] and the diastereomers, enantiomers, mixtures and salts thereof,particularly the pharmaceutically acceptable salts thereof.

[0105] A process for preparing the compounds according to the inventionis characterised in that

[0106] a) in order to prepare a compound of general formula I wherein Xdenotes an oxygen atom:

[0107] a compound of general formula

[0108] optionally formed in the reaction mixture, wherein

[0109] R¹ and R² are as defined above and

[0110] Z₁ denotes a leaving group such as tosylate, an C₁₋₄-alkylsulfonate or the like, is etherified with an alcohol of general formula

HO—Ar—Y   (III),

[0111] wherein Ar and Y are as defined above, under basic conditions or

[0112] b) in order to prepare a compound of general formula I wherein Xdenotes an oxygen atom:

[0113] a compound of general formula

[0114] optionally formed in the reaction mixture, wherein

[0115]¹ and R² are as defined above,

[0116] is etherified with an alcohol of general formula

HO—Ar—Y   (III),

[0117] wherein Ar and Y are as defined above, in the presence oftriphenylphosphine and diethyl azodicarboxylate or

[0118] c) in order to prepare a compound of general formula I wherein Xdenotes an —O—CH₂- group:

[0119] a compound of general formula IV optionally formed in thereaction mixture wherein R¹ and R² are as defined above is reacted witha compound of general formula

Z₂-CH₂-Ar—Y   (V),

[0120] wherein Ar and Y are as defined above and Z₂ denotes a leavinggroup such as a chlorine or bromine atom or a mesylate or tosylategroup, and

[0121] any protecting group used during the reactions to protectreactive groups is cleaved and/or

[0122] the group Y, if desired, may be subsequently transformed into thedesired group and/or

[0123] a compound of general formula I thus obtained is resolved intoits stereoisomers and/or

[0124] a compound of general formula I thus obtained is converted intoits salts, particularly, for pharmaceutical use, into thephysiologically acceptable salts thereof with an inorganic or organicacid or base.

[0125] Synthetic routes towards imidazoles containing substituents atposition 4 and 5 have been described starting fromp-toluenesulfonylacetonitrile which can be alkylated at the methylenebridge (Convery, M. A.; Davis, A. P.; Dunne, C. J.; MacKinnon, J. W.;Tetrahedron Lett 1995, 36 (24), 4279-4282; Tsuoda, T.; Nagaku, M.;Nagino, C.; Kawamura, Y.; Ozaki, F.; Hioki, H.; Ito, S.; TetrahedronLett 1995, 36 (14), 2531-2534). The resulting intermediate undergoesring closure with aldehydes under basic conditions resulting indihydro-oxazoles (Possel, O.; Van Leusen, A. M.; Heterocycles [HTCYAM]1977, 7, 77). These dihydro-oxazol derivatives can be transformed in afinal step by treatment with ammonia to the corresponding imidazole(Horne, D. A.; Yakushijin, K.; Buechi, G.; Heterocycles [HTCYAM] 1994,39 (1), 139-153). The residue in position 4 derives in this syntheticsequence from the used alkylbromide, the residue in position 5 of thisring system derives from the used aldehyde.

[0126] Another route to imidazoles, characterized by a methyl group inposition 5 and an n-alkyl group of at least two carbon atomsfunctionalized with a terminal hydroxy group, starts with5-methylimidazole-4-carboxyaldehyde.

[0127] Synthesis of 3-(5-methyl-1H-imidazol-4-yl)-propionic acid esterhas been outlined in Bioorg. Med. Chem. Lett. (1992, 2[12], 1509-1512).This compound can be N-tritylated with tritylchloride following standardprocedures. Subsequent treatment with lithium aluminium hydride yieldsN-trityl-3-(5-methyl-1H-imidazol-4-yl)-propan-1-ol. Substituting(carboxymethyl)-triphenylphosphonium bromide with other phosphoniumcompounds gives access to a variety of other chain lengths. Thus,phosphonium compounds containing protected alcoholes as well asphosphonium compounds functionalized with esters via linkers like alkylgroups or alkyene groups can be used in this synthesis.

[0128] General procedure according to process a)

[0129] An aromatic compound containing a phenolic hydroxy groupdissolved in a suitable solvent, for instance DMSO or DMF, is convertedinto the corresponding phenolate by addition of a base, for instance aNaH- or KH-dispersion, at about 20° C. Subsequently an N-protectedimidazole derivative functionalized with an alcohol whose hydroxy grouphas been transformed into a suitable leaving group, for instance into aC₁₋₄-alkyl sulfonate or tosylate group, is added in a molar ratio from0.7 to 1.3, preferentially in substantially stoichiometric amounts, atabout 20° C. and the mixture is then heated to 50 to 90° C.,preferentially to 70° C., for several hours. The reaction mixture isthen worked up in a suitable manner and the crude product can bepurified using known methods.

[0130] General procedure according to process b)

[0131] A substantially stoichiometric mixture of a N-protected imidazolederivative functionalized with an aliphatic alcohol, triphenylphosphineand an aromatic compound containing a phenolic hydroxy group in asuitable solvent, for instance THF or diethylether, is treated withdiethyl azodicarboxylate at about 20° C. until the reation is completed(about 10 hours to 3 days). The product is isolated and purified usingwell-known methods.

[0132] General procedure according to process c)

[0133] To a stirred solution of a N-protected imidazole derivativefuctionalized with an aliphatic alcohol in a suitable solvent, forinstance THF or diethylether, a base, for example a NaH- orKH-dispersion, and an auxiliary enhancing the solubility of the base,for instance 15-crown-5, are added at about 20° C. in order to obtainthe corresponding alcoholate. The reaction mixture is cooled to about 4°C. followed by addition of an benzylic electrophil, for example abenzylhalide or benzylmesylate, in a molar ratio of 0.7 to 1.3,preferentially in a substantially stoichiometric amount, and stirred atabout 20° C. for another 1-24 hours. The reaction mixture is then workedup in a suitable manner and the crude product can be purified usingknown methods.

[0134] General procedure for the clevage of a trityl group from animidazole residue:

[0135] The N-tritylated imidazole is dissolved in a suitable organicsolvent, for instance THF or dioxan, and 2 N HCl (1:3) before heating toabout 70° C. for 2 h. The reaction mixture is then worked up in asuitable manner, for example by removing the solvent under reducedpressure, extracting triphenylmethanol with Et₂O, neutralizing theaqueous layer with K₂CO₃ and extracting the product with Et₂O and CHCl₃.After evaporation of the solvent the combined organic extracts then givethe detritylated product.

[0136] In the reactions described hereinbefore, any reactive groupspresent such as carboxy, hydroxy, amino, alkylamino or imino groups maybe protected during the reaction by conventional protecting groups whichare cleaved again after the reaction.

[0137] For example, a protecting group for a carboxyl group may be atrimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranylgroup and

[0138] protecting groups for a hydroxy, amino, alkylamino or imino groupmay be an acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl,tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or2,4-dimethoxybenzyl group and additionally, for the amino group, aphthalyl group.

[0139] Any protecting group used is optionally subsequently cleaved forexample by hydrolysis in an aqueous solvent, e.g. in water,isopropanol/water, tetrahydrofuran/water or dioxan/water, in thepresence of a acid such as trifluoroacetic acid, hydrochloric acid orsulphuric acid or in the presence of an alkali metal base such aslithium hydroxide, sodium hydroxide or potassium hydroxide, attemperatures between 0 and 100° C., preferably at temperatures between10 and 50° C.

[0140] However, a benzyl, methoxybenzyl or benzyloxycarbonyl group iscleaved, for example, hydrogenolytically, e.g. with hydrogen in thepresence of a catalyst such as palladium/charcoal in a solvent such asmethanol, ethanol, ethyl acetate, dimethylformamide,dimethylformamide/acetone or glacial acetic acid, optionally with theaddition of an acid such as hydrochloric acid or glacial acetic acid attemperatures between 0 and 50° C., but preferably at ambienttemperature, and at a hydrogen pressure of 1 to 7 bar, but preferably 3to 5 bar.

[0141] A methoxybenzyl group may also be cleaved in the presence of anoxidising agent such as cerium(IV)ammonium nitrate in a solvent such asmethylene chloride, acetonitrile or acetonitrile/water at temperaturesof between 0 and 50° C., but preferably at ambient temperature.

[0142] A 2,4-dimethoxybenzyl group, however, is preferably cleaved intrifluoroacetic acid in the presence of anisole.

[0143] A tert.butyl or tert.butyloxycarbonyl group is preferably cleavedby treating with an acid such as trifluoroacetic acid or hydrochloricacid, optionally using a solvent such as methylene chloride, dioxan,ethyl acetate or ether.

[0144] A phthalyl group is preferably cleaved in the presence ofhydrazine or a primary amine such as methylamine, ethylamine orn-butylamine in a solvent such as methanol, ethanol, isopropanol,toluene/water or dioxan at temperatures between 20 and 50° C.

[0145] Moreover, chiral compounds of general formula I obtained may beresolved into their enantiomers and/or diastereomers.

[0146] Thus, for example, the compounds of general formula I obtainedwhich occur as racemates may be separated by methods known per se (cf.Allinger N. L. and Eliel E. L. in “Topics in Stereochemistry”, Vol. 6,Wiley Interscience, 1971) into their optical antipodes and compounds ofgeneral formula I with at least 2 asymmetric carbon atoms may beresolved into their diastereomers on the basis of theirphysical-chemical differences using methods known per se, e.g. bychromatography and/or fractional crystallisation, and, if thesecompounds are obtained in racemic form, they may subsequently beresolved into the enantiomers as mentioned above.

[0147] The enantiomers are preferably separated by column separation onchiral phases or by recrystallisation from an optically active solventor by reacting with an optically active substance which forms salts orderivatives such as e.g. esters or amides with the racemic compound,particularly acids and the activated derivatives or alcohols thereof,and separating the mixture of diastereomeric salts or derivatives thusobtained, e.g. on the basis of their differences in solubility, whilstthe free antipodes may be released from the pure diastereomeric salts orderivatives by the action of suitable agents. Optically active acids incommon use are e.g. the D- and L-forms of tartaric acid ordibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelicacid, camphorsulphonic acid, glutamic acid, N-acetylglutamic acid,aspartic acid, N-acetylaspartic acid or quinic acid. An optically activealcohol may be for example (+)- or (−)-menthol and an optically activeacyl group in amides, for example, may be a (+)- or(−)-menthyloxycarbonyl group.

[0148] Furthermore, the compounds of formula I may be converted into thesalts thereof, particularly for pharmaceutical use into thephysiologically acceptable salts with inorganic or organic acids. Acidswhich may be used for this purpose include for example hydrochloricacid, hydrobromic acid, sulphuric acid, methanesulphonic acid,phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid,tartaric acid or maleic acid.

PHARMACOLOGICAL METHODS

[0149] The ability of the compounds to interact with the histamine H3receptor was determined by the following in vitro binding assays:

[0150] Binding Assay I

[0151] Rat cerebral cortex was homogenized in ice cold K-Hepes, 5 mMMgCl₂ pH 7.1 buffer. After two differential centrifugations the lastpellet was resuspended in fresh Hepes buffer containing 1 mg/mLbacitracin. Aliquots of the membrane suspension (400 mg/mL) wereincubated for 60 min at 25° C. with 30 pM [¹²⁵I]-iodoproxifan, a knownhistamine H3 receptor antagonist, and the test compound at variousconcentrations. The incubation was stopped by dilution with ice-coldmedium, followed by rapid filtration through Whatman GF/B filterspretreated for 1 h with 0.5% polyethyleneimine. The radioactivityretained on the filters was counted using a Cobra II auto gamma counter.The radioactivity of the filters was indirectly proportional to thebinding affinity of the tested compound. The results were analyzed bynonlinear regression analysis.

[0152] Binding Assay II

[0153] The H3-receptor agonist ligand R-α-methyl[³H]histamine wasincubated with isolated rat cortex cell-membranes at 25° C. for 1 h,followed by a filtration of the incubate through Whatman GF/B filters.Radioactivity retained on the filters was measured using a beta counter.Male Wistar rats (150-200 g) were decapitated and cerebral cortex wasquickly dissected out and frozen immediately on dry ice. Tissue was keptat −80° C. until membrane preparation. During the membrane preparationthe tissue was kept on ice all the time. Rat cerebral cortex washomogenized in 10 volumes (w/w) ice-cold Hepes buffer (20 mM Hepes, 5 mMMgCl₂ pH 7.1 (KOH)+1 mg/ml bacitracin) using a Ultra-Turrax homogenizerfor 30 seconds. The homogenate was centrifuged at 140 g in 10 min. Thesupernatant was transferred to a new test tube and centrifuged for 30min at 23000 g. Pellet was resuspended in 5-10 ml Hepes buffer,homogenized and centrifuged for 10 min at 23000 g. This shortcentrifugation step is repeated twice. After the last centrifugation thepellet was resuspended in 2-4 ml Hepes buffer and the proteinconcentration was determined. The membranes were diluted to a proteinconcentration of 5 mg/ml using Hepes buffer, aliquoted and stored at−80° C. until use.

[0154] 50 μL test-compound, 100 μl membrane (200 mg/ml), 300 μl Hepesbuffer and 50 μl R-α-methyl[³H]histamine (1 nM) were mixed in a testtube. The compounds to be tested were dissolved in DMSO and furtherdiluted in H₂O to the desired concentrations. Radioligand and membraneswere diluted in Hepes buffer+1 mg/ml bacitracin. The mixture wasincubated for 60 min at 25° C. Incubation was terminated by adding 5 mlice-cold 0.9% NaCl, followed by rapid filtration through Whatman GF/Bfilters pre-treated for 1 h with 0.5% polyethyleneimine. The filterswere washed with 2×5 ml ice-cold NaCl. To each filter a 3 mlscintillation cocktail was added and the radioactivity retained wasmeasured with a Packard Tri-Carb beta counter.

[0155] IC₅₀ values were calculated by non-linear regression analysis ofbinding curves (6 points minimum) using the windows program GraphPadPrism, GraphPad software, USA.

[0156] When tested, the present compounds of the formula (I) generallyshowed a high binding affinity to the histamine H3 receptor.

[0157] Preferably, the compounds according to the invention have an IC₅₀value as determined by one or both of the assays of less than 1 μM, morepreferred of less than 500 nM and even more preferred of less than 100nM.

[0158] Binding Assay III

[0159] The H3 receptor was cloned by PCR and subcloned into the pcDNA3expression vector. Cells stably expressing the H3 receptor weregenerated by transfecting the H3-expression vectors into HEK 293 cellsand using G418 to select for H3 clones. The h-H3-HEK 293 clones werecultured in DMEM with glutamax, 10% FCS, 1% Pen/Strep and 1 mg/ml G 418at 37° C. and 5% CO₂. Before harvesting, the confluent cells were rinsedwith PBS and incubated with Versene for approximately 5 minutes. Thecells were flushed with PBS and DMEM and the cellsuspension collected ina tube and centrifuged for 5-10 min at 1500 rpm in a Heraeus SepatechMegafuge 1.0. The pellet was resuspended in 10-20 vol. Hepes buffer (20mM Hepes, 5 mM MgCl₂, pH 7.1 (KOH)) and homogenized for 10-20 secondsusing a Ultra-Turrax homogenizer. The homogenate was centrifuged for 30min at 23000 g. The pellet was resuspended in 5-10 ml Hepes buffer,homogenized 5-10 seconds with the Ultra-Turrax and centrifuged for 10min at 23000 g. Following this centrifugation step, the membrane pelletwas resuspended in 2-4 ml Hepes buffer, homogenized with a syringe orteflonhomogenizer, and the protein concentration determined. Themembranes were diluted to a protein concentration of 1-5 mg/ml in Hepesbuffer, aliquoted and kept at −80° C. until use.

[0160] Aliquots of the membrane suspension were incubated for 60 min at25° C. with 30 pM [¹²⁵I]-iodoproxifan, a known compound with highaffinity for the H3 receptor, and the test compound at variousconcentrations. The incubation was stopped by dilution with ice-coldmedium, followed by rapid filtration through Whatman GF/B filterspretreated for 1 h with 0.5% polyethyleneimine. The radioactivityretained on the filters was counted using a Cobra II auto gamma counter.The radioactivity of the filters was indirectly proportional to thebinding affinity of the tested compound. The results were analyzed bynonlinear regression analysis.

[0161] Preferably, the compounds according to the invention have an IC₅₀value as determined by the assay of less than 1 μM, more preferred ofless than 500 nM and even more preferred of less than 100 nM.

[0162] IC₅₀ of Example 15/5 (see below): <100 nM

[0163] IC₅₀ of Example 16/14 (see below): <50 nM

[0164] Furthermore, in a similar way binding assays were carried out inorder to determine the ability of the present compounds to interact withthe histamine H1 receptor (reference compound [¹²⁵I]-pyrilamine) and thehistamine H2 receptor (reference compound [¹²⁵]-aminopotentidine),respectively. These assays showed that the present compounds do not showa high affinity for these receptors and hence are very specific to thehistamine H3 receptor.

[0165] Functional Assay

[0166] The ability of the compounds to interact with the histamine H3receptor as agonists, inverse agonists and/or competitive antagonists,was determined by an in vitro functional assay utilizing membranes fromHEK293 cell expressing the human H3 receptors.

[0167] The H3 receptor was cloned by PCR and subcloned into the pcDNA3expression vector. Cells stably expressing the H3 receptor weregenerated by transfecting the H3-expression vectors into HEK 293 cellsand using G418 to select for H3 clones. The h-H3-HEK 293 clones werecultured in DMEM with glutamax, 10% FCS, 1% Pen/Strep and 1 mg/ml G 418at 37° C. and 5% CO₂.

[0168] The H3 receptor expressing cells were washed once with phosphatebuffered saline (PBS) and harvested using versene (GIBCO-BRL). PBS wasadded and the cells were centrifuged for 5 min at 188 g. The cell pelletwas resuspended in stimulation buffer to a concentration of 1×10⁶cells/ml. cAMP accumulation was measured using the Flash Plate® cAMPassay (NEN™ Life Science Products). The assay was generally performed asdescribed by the manufacturer. Briefly, 50 μl cell suspension was addedto each well of the Flashplate which also contained 25 μl 40 μMisoprenaline, to stimulate cAMP generation, and 25 μl of test compound(either agonists or inverse agonists alone, or agonist and competitiveantagonist in combination). The final volume in each well was 100 μl.Test compounds were dissolved in DMSO and diluted in H₂O. The mixturewas shaken for 5 minutes, and allowed to stand for 25 minutes at roomtemperature. The reaction was stopped with 100 μl “Detection Mix” perwell. The plates were then sealed with plastic, shaken for 30 minutes,allowed to stand overnight, and finally the radioactivity was counted inthe Cobra II auto gamma topcounter. EC₅₀ values were calculated bynon-linear regression analysis of dose response curves (6 pointsminimum) using GraphPad Prism. Kb values were calculated by Schild plotanalysis.

[0169] EC₅₀ of Example 15/5 (see below): <100 nM

[0170] EC₅₀ of Example 16/14 (see below): <50 nM

PHARMACEUTICAL COMPOSITIONS

[0171] The compounds of the invention may be administered alone or incombination with pharmaceutically acceptable carriers or excipients, ineither single or multiple doses. The pharmaceutical compositionsaccording to the invention may be formulated with pharmaceuticallyacceptable carriers or diluents as well as any other known adjuvants andexcipients in accordance with conventional techniques such as thosedisclosed in Remington: The Science and Practice of Pharmacy, 19^(th)Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.

[0172] The pharmaceutical compositions may be specifically formulatedfor administration by any suitable route such as the oral, rectal,nasal, pulmonary, topical (including buccal and sublingual),transdermal, intracisternal, intraperitoneal, vaginal and parenteral(including subcutaneous, intramuscular, intrathecal, intravenous andintradermal) route, the oral route being preferred. It will beappreciated that the preferred route will depend on the generalcondition and age of the subject to be treated, the nature of thecondition to be treated and the active ingredient chosen.

[0173] Pharmaceutical compositions for oral administration include soliddosage forms such as capsules, tablets, dragees, pills, lozenges,powders and granules. Where appropriate, they can be prepared withcoatings such as enteric coatings or they can be formulated so as toprovide controlled release of the active ingredient such as sustained orprolonged release according to methods well-known in the art.

[0174] Liquid dosage forms for oral administration include solutions,emulsions, suspensions, syrups and elixirs.

[0175] Pharmaceutical compositions for parenteral administration includesterile aqueous and non-aqueous injectable solutions, dispersions,suspensions or emulsions as well as sterile powders to be reconstitutedin sterile injectable solutions or dispersions prior to use. Depotinjectable formulations are also contemplated as being within the scopeof the present invention.

[0176] Other suitable administration forms include suppositories,sprays, ointments, cremes, gels, inhalants, dermal patches, implantsetc.

[0177] A typical oral dosage is in the range of from about 0.001 toabout 100 mg/kg body weight per day, preferably from about 0.01 to about50 mg/kg body weight per day, and more preferred from about 0.05 toabout 10 mg/kg body weight per day administered in one or more dosagessuch as 1 to 3 dosages. The exact dosage will depend upon the frequencyand mode of administration, the sex, age, weight and general conditionof the subject treated, the nature and severity of the condition treatedand any concomitant diseases to be treated and other factors evident tothose skilled in the art.

[0178] The formulations may conveniently be presented in unit dosageform by methods known to those skilled in the art. A typical unit dosageform for oral administration one or more times per day such as 1 to 3times per day may contain of from 0.05 to about 1000 mg, preferably fromabout 0.1 to about 500 mg, and more preferred from about 0.5 mg to about200 mg.

[0179] For parenteral routes, such as intravenous, intrathecal,intramuscular and similar administration, typically doses are in theorder of about half the dose employed for oral administration.

[0180] The compounds of this invention are generally utilized as thefree substance or as a pharmaceutically acceptable salt thereof. Oneexample is an acid addition salt of a compound having the utility of afree base. When a compound according to the invention contains a freebase such salts are prepared in a conventional manner by treating asolution or suspension of a free base of the compound according to theinvention with a chemical equivalent of a pharmaceutically acceptableacid, for example, inorganic and organic acids. Representative examplesare mentioned above. Physiologically acceptable salts of a compound witha hydroxy group include the anion of said compound in combination with asuitable cation such as sodium or ammonium ion.

[0181] For parenteral administration, solutions of the present compoundsin sterile aqueous solution, aqueous propylene glycol or sesame orpeanut oil may be employed. Such aqueous solutions should be suitablebuffered if necessary and the liquid diluent first rendered isotonicwith sufficient saline or glucose. The aqueous solutions areparticularly suitable for intravenous, intramuscular, subcutaneous andintraperitoneal administration. The sterile aqueous media employed areall readily available by standard techniques known to those skilled inthe art.

[0182] Suitable pharmaceutical carriers include inert solid diluents orfillers, sterile aqueous solution and various organic solvents. Examplesof solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc,gelatine, agar, pectin, acacia, magnesium stearate, stearic acid orlower alkyl ethers of cellulose. Examples of liquid carriers are syrup,peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines,polyoxyethylene or water. Similarly, the carrier or diluent may includeany sustained release material known in the art, such as glycerylmonostearate or glyceryl distearate, alone or mixed with a wax. Thepharmaceutical compositions formed by combining the compounds accordingto the invention and the pharmaceutically acceptable carriers are thenreadily administered in a variety of dosage forms suitable for thedisclosed routes of administration. The formulations may conveniently bepresented in unit dosage form by methods known in the art of pharmacy.

[0183] Formulations of the present invention suitable for oraladministration may be presented as discrete units such as capsules ortablets, each containing a predetermined amount of the activeingredient, and which may include a suitable excipient. Theseformulations may be in the form of powder or granules, as a solution orsuspension in an aqueous or non-aqueous liquid, or as an oil-in-water orwater-in-oil liquid emulsion.

[0184] If a solid carrier is used for oral administration, thepreparation may be tabletted, placed in a hard gelatine capsule inpowder or pellet form or it can be in the form of a troche or lozenge.The amount of solid carrier will vary widely but will usually be fromabout 25 mg to about 1 g. If a liquid carrier is used, the preparationmay be in the form of a syrup, emulsion, soft gelatine capsule orsterile injectable liquid such as an aqueous or non-aqueous liquidsuspension or solution.

[0185] If desired, the pharmaceutical composition of the invention maycomprise the compound of the formula I in combination with furtherpharmacologically active substances.

[0186] The following examples shall illustrate the invention withoutlimiting the scope of the invention. Examples 1, 2 and 4 to 14 describethe preparation of starting materials or intermediates. The compounds ofExamples 3, 15, 16 and 17 including the compounds prepared analogouslyare pharamceutically active compounds according to the invention.

[0187] Abbreviations:

[0188] Ac: acetyl residue

[0189] DCM: dichloromethane, methylenechloride

[0190] DMF: N,N-dimethyl formamide

[0191] DMSO: dimethyl sulfoxide

[0192] EDC: N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0193] HOBt: N-hydroxybenzotriazole, 1-hydroxybenzotriazole

[0194] MP: melting point

[0195] NMP: N-methylpyrrolidone

[0196] SiO₂: silica

[0197] TBAF: tetrabutylammoniumfluoride

[0198] TBDMS: tert-Butyldimethylsilyl residue

[0199] THF: tetrahydrofuran

[0200] TLC: thin layer chromatography

[0201] Tosmic: p-toluenesufonylmethyl isocyanide

[0202] Tr: Trityl residue

EXAMPLES Example 1 N-Trityl-3-(5-methyl-1H-imidazol-4-yl)-propan-1-ol

[0203] Trityl-3-(5-methyl-1H-imidazol-4-yl)-propan-1-ol was synthesizedaccording to Scheme 1 following the following procedure:

[0204] a) Preparation of 3-(3H-imidazol-4-yl)-propionic acid ester hasbeen carried out following the synthetic procedure described in Bioorg.Med. Chem. Lett. 1992, 2(12), 1509-1512.

[0205] b) To a solution of 3-(3H-imidazol-4-yl)-propionic acid ester (97mmol) in acetonitrile (250 ml) were added triethylamine (27 ml, 194mmol) and a solution of tritylchloride (40.6 g, 146 mmol) inacetonitrile (500 ml). The resulting mixture was stirred at 20° C.overnight. The mixture was concentrated under reduced pressure and theresidue redissolved in ethylacetate, washed with water (2×) and brine(1×) and concentrated under reduced pressure.

[0206] c) To a solution of N-trityl-3-(3H-imidazol-4-yl)-propionic acidester (32 mmol) in THF (100 ml) was added lithium aluminium hydride (24ml, 1 mol/l in THF, 24 mmol). The mixture was stirred at 20° C. for 45min, and water (3.5 ml) and NaOH (35 ml, 4 mol/l in water) werecarefully added. Water (14 ml) was added before neutralization of thesolution with aqueous HCl, filtration and concentration under reducedpressure.

Example 2 3-(5-Methyl-1H-imidazol-4-yl)-propan-1-ol hydrochloride

[0207]

[0208] A solution of 29 mmol of example 1 in 40 ml ethanol and 130 ml 2MHCl was refluxed for 2 h and completion of the reaction was monitored byTLC. After removal of the solvent under reduced pressure, the crudeproduct was extracted twice with ethyl acetate in order to removetritanol and the residue dried in vacuo.

Example 3/1 5-Methyl-4-(3-phenoxy-propyl)-1H-imidazole

[0209]

[0210] A mixture of example 1 (1.9 g, 5 mmol), triphenylphosphine (1.6g, 6 mmol), and phenol (0.47 g, 5 mmol) was dissolved in 20 mL offreshly distilled dry THF under nitrogen and cooling. A solution ofdiethyl azodicarboxylate (1.1 g, 6 mmol) in 4 mL of THF was added tothis mixture and the reaction mixture stirred at ambient temperature for48 h. After removal of the solvent under reduced pressure and silica gelcolumn chromatography using ethyl acetate, the residue was dissolved in10 ml of THF and 30 mL of 2 N HCl. The reaction mixture was heated at70° C. for 2 h. The solvent was evaporated under reduced pressure, andtriphenylmethanol was extracted with Et₂O. The aqueous layer wasneutralized with K₂CO₃ and the product extracted with Et₂O and CHCl₃.The combined organic extracts were dried and evaporated to give an oil.exam- ple structure Name 3/1

5-Methyl-4-(3-phenoxy- propyl)-1H-imidazole

[0211] Mass Spectrometry: [M+H]⁺ 217

[0212]¹H-NMR (300 MHz, CDCl₃): 2.0-2.2 (m, 5H); 2.74 (t, 2H); 3.93 (t,2H); 6.8-6.97 (m, 3H); 7.28-7.30 (m, 2H); 7.52 (s, 1H).

[0213] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,50

[0214] MP: 109° C.

Examples 3/2-3/21

[0215] Examples 3/2 to 3/22 were prepared according to the proceduredescribed for example 3/1. exam- ple structure Name 3/2

4-[3-(4-Ethynyl-phenoxy)- propyl]-5-methyl-1H-imidazole

[0216] Example 3/2 has been prepared starting from example 1 and4-ethynyl-phenol. (4-Ethynyl-phenol has been prepared according toCevasco, Giorgio; Pardini, Roberto; Thea, Sergio; Eur.J. Org. Chem.; 4;1998; 665-670.)

[0217] Mass Spectrometry: [M+H]⁺ 242

[0218] Mass Spectrometry: [M−H]⁻ 239

[0219]¹H-NMR (300 MHz, CD₃OD): 2.0-2.1 (m, 5H); 2.72 (t, 2H); 3.93 (t,2H); 6.83-6.86 (d, 2H); 7.34-7.37 (d, 2H); 7.57 (s, 1 H).

[0220] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,47

[0221] MP: 85° C. exam- ple structure Name 3/3

1-{4-[3-(5-Methyl-1H- imidazol-4-yl)-propoxy]- phenyl}-ethanone

[0222] Example 3/3 has been prepared starting from example 1 and4-hydroxyacetophenone.

[0223] Mass Spectrometry: [M+H]⁺ 259

[0224] Mass Spectrometry: [M−H]⁻ 257

[0225]¹H-NMR (300 MHz, CDCl₃): 2.08-2.2 (m, 5H); 2.53 (s, 3H); 2.76 (t,2H); 3.98 (t, 2H); 6.85-89 (d, 2H); 7.86-7.9 (d, 2 H); 7.63 (s, 1H).

[0226] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,46

[0227] MP: 96° C. exam- ple structure Name 3/4

Cyclopropyl-{4-[3-(5- methyl-1H-imidazol-4- yl)-propoxy]-pheny1}-methanone

[0228] Example 3/4 has been prepared starting from example 1 andcyclopropyl-(4-hydroxy-phenyl)-methanone.(Cyclopropyl-(4-hydroxy-phenyl)-methanone has been prepared according toRastogi, S. N. et al.; J. Med. Chem.; EN; 15; 1972; 286-291.)

[0229] Mass Spectrometry: [M+H]⁺ 285

[0230] Mass Spectrometry: [M−H]⁻ 283

[0231]¹H-NMR (300 MHz, CDCl₃): 0.96-1.03 (m, 2H); 1.16-2.03 (m, 2H);2.08-2.20 (m, 5H); 2.57-2.66 (m, 2H); 3.76 (t, 2H); 3.98 (t, 2H); 6.90(d, 2H); 7.61 (s, 1H); 7.95 (d, 5 2H).

[0232] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,47

[0233] MP: 91° C. exam- ple structure Name 3/5

4-[3-(5-Methyl-1H- imidazol-4-yl)-propoxy]- benzonitrile

[0234] Example 3/5 has been prepared starting from example 1 and4-cyanophenol.

[0235] Mass Spectrometry: [M+H]⁺ 242

[0236] Mass Spectrometry: [M−H]⁻ 239

[0237] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,48 exam- plestructure Name 3/6

4-[3-(4-Fluoro-phenoxy)- propyl]-5-methyl-1H- imidazole

[0238] Example 3/6 has been prepared starting from example 1 and4-fluorophenol.

[0239] Mass Spectrometry: [M+H]⁺ 235

[0240] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,51

[0241] MP: 106° C. exam- ple structure Name 3/7

4-[3-(4-Iodo-phenoxy)- propyl]-5-methyl-1H- imidazole

[0242] Example 3/7 has been prepared starting from example 1 and4-iodophenol.

[0243] Mass Spectrometry: [M+H]⁺ 343

[0244] Mass Spectrometry: [M−H]⁻ 341

[0245] TLC (solvent: DCM/MeOH=95:5 Polygram ALOX), R_(f): 0,48 exam- plestructure Name 3/8

4-[3-(4-tert-Butyl- phenoxy)-propyl]-5-methyl- 1H-imidazole

[0246] Example 3/8 has been prepared starting from example 1 and4-tert-butylphenol.

[0247] Mass Spectrometry: [M+H]⁺ 273

[0248]¹H-NMR (300 MHz, CDCl₃): 1.28 (s, 9 H); 2.05-2.13 (m, 2H); 2.16(s, 3H); 2.70-2.77 (t, 2H); 3.92 (t, 2H); 6.82 (d, 2H); 7.26 (d, 2H);7.45 (s, 1H).

[0249] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,53

[0250] MP:97° C. Exam- ple structure Name 3/9

5-Methyl-4-[3-(4- trifluoromethyl- phenoxy)-propyl]-1H- imidazole

[0251] Example 3/9 has been prepared starting from example 1 and4-(trifluormethyl)phenol.

[0252] Mass Spectrometry: [M+H]⁺ 285

[0253] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,51

[0254] MP: 98° C. Exam- ple structure Name 3/10

5-Methyl-4-[3-(4- trifluoromethoxy-phenoxy)- propyl]-1H-imidazole

[0255] Example 3/10 has been prepared starting from example 1 and4-(trifluormethoxy)phenol.

[0256] Mass Spectrometry: [M+H]⁺ 301

[0257] Mass Spectrometry: [M−H]⁻ 299

[0258] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,52 Exam- plestructure Name 3/11

4-[3-(Benzo[1,3]dioxol- 5-yloxy)-propyl]-5-methyl- 1H-imidazole

[0259] Example 3/11 has been prepared starting from example 1 andsesamol.

[0260] Mass Spectrometry: [M+H]⁺ 261

[0261] Mass Spectrometry: [M−H]⁻ 259

[0262] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,54 exam- plestructure Name 3/12

4-[3-(4-Imidazol-1-yl- phenoxy)-propyl]-5-me- thyl-1H-imidazole

[0263] Example 3/12 has been prepared starting from example 1 and4-(imidazol-1-yl)phenol.

[0264] Mass Spectrometry: [M+H]⁺ 283

[0265] Mass Spectrometry: [M−H]⁻ 281

[0266]¹H-NMR (300 MHz, CDCl₃): 2.11 (p, 2H); 2.17 (s, 3H); 2.74 (t, 2H);3.97 (t, 2H); 6.90-6.97 (m, 2H); 7.14-7.29 (m, 4H); 7.47 (s, 1H); 7.74(s, 1H).

[0267] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,31

[0268] MP: 158° C. exam- ple structure Name 3/13

8-[3-(5-Methyl- 1H-imidazol-4- yl)-propoxy]- 2,3,6,7-tetrahy-dro-1H,5H-py- rido[3,2,1-ij]- quinoline

[0269] Example 3/13 has been prepared starting from example 1 and8-hydroxyjujolidine.

[0270] Mass Spectrometry: [M+H]⁺ 312

[0271] Mass Spectrometry: [M−H]⁻ 311

[0272]¹H-NMR (300 MHz, CDCl₃): 1.89-2.01 (m, 4H); 2.02-2.12 (m, 2H);2.17 (s, 3H); 2.64-2.81 (m, 6H); 3.04-3.12 (m, 4H); 3.88 (t, 2H); 6.07(d, 1H); 6.69 (d, 1H); 7.61 (s, 1H).

[0273] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,46 exam- plestructure Name 3/14

4-[3-(Biphenyl-4-yl- oxy)-propyl]-5-methyl- 1H-imidazole

[0274] Example 3/14 has been prepared starting from example 1 and4-phenylphenol.

[0275] Mass Spectrometry: [M+H]⁺ 293

[0276] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,45

[0277] MP: 169° C. exam- ple structure Name 3/15

6-[3-(5-Methyl-1H-imi- dazol-4-yl)-propoxy]- 3,4-dihydro-2H-naph-thalen-1-one

[0278] Example 3/15 has been prepared starting from example 1 and6-hydroxy-1-tetralone.

[0279] Mass Spectrometry: [M+H]⁺ 285

[0280] Mass Spectrometry: [M−H]⁻ 283

[0281] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,41 exam- plestructure Name 3/16

2-Methyl-5-[3-(5-methyl- 1H-imidazol-4-yl)- propoxy]-benzothiazole

[0282] Example 3/16 has been prepared starting from example 1 andmethyl-5-benzothiazolol.

[0283] Mass Spectrometry: [M+H]⁺ 288

[0284] Mass Spectrometry: [M−H]⁻ 285

[0285] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,38

[0286] MP: 106° C. exam- ple structure Name 3/17

5-Methyl-4-[3-(naph- thalen-2-yloxy)-propyl]- 1H-imidazole

[0287] Example 3/17 has been prepared starting from example 1 and2-naphthol.

[0288] Mass Spectrometry: [M+H]⁺ 267

[0289] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,33

[0290] MP: 108° C. exam- ple structure Name 3/18

5-Methyl-4-[3-(5,6,7,8- tetrahydro-naphthalen-2- yloxy)-propyl]-1H-imidazole

[0291] Example 3/18 has been prepared starting from example 1 and5,6,7,8-tetrahydro-2-naphthol.

[0292] Mass Spectrometry: [M+H]⁺ 271

[0293] Mass Spectrometry: [M−H]⁻ 270

[0294] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f: 0,42) exam- plestructure Name 3/19

6-[3-(5-Methyl-1H-imi- dazol-4-yl)-propoxy]- quinoline

[0295] Example 3/19 has been prepared starting from example 1 and6-hydroxyquinoline.

[0296] Mass Spectrometry: [M+H]⁺ 268

[0297] Mass Spectrometry: [M−H]⁻ 266

[0298] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,44 exam- plestructure Name 3/20

4-[3-(5-Methyl-1H-imi- dazol-4-yl)-propoxy]- pyridine

[0299] Example 3/20 has been prepared starting from example 1 and4-hydroxypiperidine.

[0300] Mass Spectrometry: [M+H]⁺ 218

[0301] Mass Spectrometry: [M−H]⁻ 216

[0302] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,18 exam- plestructure Name 3/21

2-[3-(5-Methyl-1H- imidazol-4-yl)-propoxy]- pyridine

[0303] Example 3/21 has been prepared starting from example 1 and2-hydroxypiperidine.

[0304] Mass Spectrometry: [M+H]⁺218

[0305]¹H-NMR (300 MHz, D₆-DMSO): 1.91 (m, 2H); 1.98 (s, 3H); 2.52 (t,2H); 4.16 (t, 2H); 6.76-6.84 (m, 1H); 6.88-6.97 (m, 1H); 7.35 (s, 1H);7.61-7.70 (m, 1H); 8.89-8.91 (d, 1H).

[0306] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,25

Example 4 5-Methyl-4-(4-tert-butyldimethylsilanyloxy-butyl)-1H-imidazole

[0307]

[0308] a) To a flame dried flask was added dried powdered molecularsieves (35 g) and 39.2 g (0.575 mol) imidazole and DMF (125 ml). To thestirred suspension was added 3-bromo-1-propanol (20.1 ml, 0.23 mol) anda solution of tert-butyldimethylchlorosilane (41.6 g, 0.276 mol) in DMF(125 ml) at room temperature. The reaction mixture was stirred for 2hours, filtered and extracted twice with hexane. The hexane phase waswashed with water, saturated NaCl-solution, dried (Na₂SO₄) andevaporated. The residue was chromatographed on SiO₂ with hexane to yieldthe silylated 3-bromo-1-propanol (44.0 g, 75.5%) as a colorless liquid.

[0309] b) A mixture of this intermediate (7.7 g, 30.7 mmol) andtriphenylphosphine (8.9 g, 33.8 mmol) in benzene was stirred for 72hours at 80° C. After cooling the reaction mixture was evaporated andthe residue chromatographed on SiO₂ with with a gradient of CH₂Cl₂ toCH₂Cl₂/MeOH (20:1) to yield[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-triphenyl-phosphoniumbromide (7.82 g) as a colourless powder.

[0310]¹H-NMR (300 MHz, CDCl₃): 7.87-7.65 (m, 15 arom. H); 3.92-3.83 (m,4H, 2 CH₂); 1.94-1.1.86 (m, 2H, 1 CH₂); 0.85 (s, 9H, tBu); 0.03 (s, 2CH₃).

[0311] c) To a stirred suspension of[3-(tert-butyl-dimethyl-silanyloxy)-propyl]-triphenyl-phosphoniumbromide (7.5 g, 14.6 mmol) in THF was added under argon at −78° C. asolution of nBuLi (10.0 ml, 16.0 mmol, 1.6 M in hexane). The orangecolored reaction mixture was stirred for 1 hour at −78° C. (whichresulted in a clear solution) and 2-methyl-imidazole-3-carboxaldehydewas added in portions. The reaction mixture was stirred for 10 minutesat −78° C., for 20 hours at room temperature and for 8 hours heatedunder reflux. The reaction mixture was evaporated and the residuechromatographed on SiO₂ with a gradient form EtOAc to a mixture of EtOAcand EtOH (4:1) to yield5-[-4-(tert-butyl-dimethyl-silanyloxy)-but-1-enyl]-4-methyl-1H-imidazole(1.82 g, 51.9%) as a slightly yellow oil.

[0312] d) A mixture of5-[-4-(tert-Butyl-dimethyl-silanyloxy)-but-1-enyl]-4-methyl-1H-imidazole(1.68 g, 6.3 mmol) and 10% Pd/C (255 mg) in acetic acid was hydrogenated(H₂ balloon) for 15 hours, filtered through celite and the filterresidue washed with acetic acid and methanol. The filtrate wasevaporated and the residue extracted with EtOAc and 2M aqueous Na₂CO₃solution. The organic phase was dried (Na₂SO₄) and evaporated to yield5-Methyl-4-(4-tert-butyl-dimethylsilanyloxy-butyl)-1H-imidazole (1.64 g)as slightly yellow oil.

[0313]¹H-NMR (300 MHz, CDCl₃): 7.58 (s, 1H, H-C2); 5.98 (br.s, NH); 3.64(t, J=6.1, 2H, OCH₂); 2.59 (t, J=7.3, 2H, CH₂-C4); 2.21 (s, 3H, CH₃-C5);1.72-1.50 (m, 4H, 2 CH₂); 0.89 (s, 9H, tBu); 0.05 (s, 2 CH₃).

Example 5 4-(N-Trityl-5-methyl-1H-imidazol-4-yl)-butanol

[0314]

[0315] a) To a solution of5-methyl-4-(4-tert-butyldimethylsilanyloxy-butyl)-1H-imidazole (10 mmol)in acetonitrile (25 ml) were added triethylamine (2.7 ml, 19.4 mmol) anda solution of tritylchloride (4 g, 15 mmol) in acetonitrile (50 ml). Theresulting mixture was stirred at 20° C. overnight. The mixture wasconcentrated under reduced pressure and the residue redissolved inethylacetate, washed with water (2×) and brine (1×) and concentratedunder reduced pressure.

[0316] b) To a stirred solution of the tritylated product (2.0 g, 3.9mmol, as mixture of trityl isomers) in THF (40 ml) was added at roomtemperature TBAF×3H₂O (1.6 g, 5.1 mmol). After 1.5 and 4.5 hours anothertwo portions of TBAF×3H₂O (800 mg, 2.55 mmol) were added and thereaction mixture was stirred for 5.5 hours and evaporated. The residuewas chromatographed on SiO₂ (deactivated with Et₃N) with a gradient ofEtOAc/hexane (1:1) to EtOAc yielding example 5 (1.42 g, 91.6%) ascolorless powder.

[0317]¹H-NMR (300 MHz, DMSO-d6): 7.44-7.36 (m, 9 arom. H); 7.07-6.97 (m,6 arom. H, H-C2); 4.32 (t, J=5.2, 1H, OH); 3.36 (br.qa, J=5.2, 6.2; 1H,CH₂O); 2.35 (t, J=7.2, 2H, CH₂-C4); 1.58-1.32 (m, 4H, 2 CH₂); 1.30 (s,3H, CH₃-C5).

Example 6 5-Methyl-4-(2-tert-butyldimethylsilanyloxy-ethyl)-1H-imidazole

[0318]

[0319] a) The TBDMS protected alcohol was prepared from 2-bromo-ethanolusing the procedure described in 4 a).

[0320] b) In a dried flask NaH-dispersion (7.4 g, ˜0.170 mol) was washedtwice with hexane and suspended in Et₂O (90 ml) and DMSO (270 ml) andcooled to 4° C. To the reaction mixture was added a solution of Tosmic(30 g, 0.153 mol) in a mixture of DMSO (180 ml) and Et₂O (60 ml) andstirred for 5 minutes, followed by addition of a solution of thesilylated 2-bromo-ethanol (42.8 g, 0.169 mol) in Et₂O (150 ml) wherebythe temperature was held between 10-15° C. The reaction mixture wasstirred for 45 minutes at room temperature, poured onto cooled water(750 ml) and extracted twice with EtOAc (1 l). The combined organicfractions were washed with water and saturated brine, dried (Na₂SO4),evaporated and the residue chromatographed on SiO₂ with a gradient ofhexane to hexane/EtOAc 4:1) to yield[3-TBDMS-1-(toluene-4-sulfonyl)-propyl]-isocyanide (35.0 g, 64.1%) as aclear oil. ¹H-NMR (300 MHz, CDCl₃): 7.87 (d, J=8.2, 2 arom. H); 7.42 (d,J=8.1, 2 arom. H); 4.76 (dd, J=3.3, 11.0, 1H); 3.92-3.71 (m, 2H, OCH₂);2.49 (s, 3H, CH₃); 2.49-2.40 (m, 1H); 1.94-1.83 (m, 1H); 0.88 (s, 9H,tBu); 0.06 (s, 6H, 2 CH₃).

[0321] c) To [4-TBDMS-1-(toluene-4-sulfonyl)-butyl]-isocyanid (7.0 mmol)was added THF (25 ml), acetaldehyde (7.7 mmol) and KOtBu (250 mg) atroom temperature (reaction slightly exothermic). The reaction mixturewas stirred for 20 minutes at room temperature, the solvent was removedand the residue dissolved in saturated methanolic ammonia (25 ml) andheated at 100° for 5 hours in a sealed tube. After cooling to roomtemperature the solvent was removed and the residue chromatographed onSiO₂ with a gradient from EtOAc to EtOAc and ethanol (7:3) is yieldingexample 6 (33%) as a slighly yellow oil.

[0322]¹H-NMR (300 MHz, CDCl₃): 7.57 (s, 1H, H-C2); 6.14 (br.s, NH); 3.83(t, J=6.0, 2H, OCH₂); 2.76 (t, J=6.0, 2H, CH₂-C4); 2.20 (s, 3H, CH₃-C5);0.88 (s, 9H, tBu); 0.03 (s, 6H, 2 CH₃).

Example 7 2-(N-Trityl-5-methyl-1H-imidazol-4-yl)-ethanol

[0323]

[0324] a) To a solution of5-methyl-4-(2-tert-butyldimethylsilanyloxy-ethyl)-1H-imidazole (30 g,125 mmol) in acetonitrile (300 ml) were added triethylamine (34 ml, 250mmol) and a solution of tritylchloride (52.3 g, 188 mmol) inacetonitrile (600 ml). The resulting mixture was stirred at 20° C.overnight. The mixture was concentrated under reduced pressure and theresidue redissolved in ethylacetate, washed with water (2×) and brine(1×) and concentrated under reduced pressure.

[0325] b) To a stirred solution of the tritylated product (2.0 g, 3.9mmol, as mixture of trityl isomers) in THF (40 ml) was added at roomtemperature TBAF×3H₂O (1.6 g, 5.1 mmol). After 1.5 and 4.5 hours anothertwo portions of TBAF×3H₂O (800 mg, 2.55 mmol) were added and thereaction mixture was stirred for 5.5 hours and evaporated. The residuewas chromatographed on SiO₂ (deactivated with Et₃N) with a gradient ofEtOAc/hexane (1:1) to EtOAc yielding example 7 (1.42 g, 91.6%) ascolorless powder.

Example 8 5-Ethyl-4-(3-tert-butyldimethylsilanyloxy-propyl)-1H-imidazole

[0326]

[0327] a) In a first step tosmic was alkylated with the silylated3-bromo-1-propanol, described in the preparation of example 4, using thesame reaction conditions as described for the respective precursor ofexample 6.

[0328]¹H-NMR (300 MHz, CDCl₃): 7.86 (d, J˜8.1, 2 arom. H); 7.42 (d,J˜7.9, 2 arom. H); 4.69 (dd, J=3.4, 10.5, H-Cl); 3.75-3.60 (m, 2H,OCH₂); 2.49 (s, 3H, CH₃); 2.37-2.26 (m, 1H); 1.98-1.67 (m, 3H); 0.86 (m,9H, tBu); 0.04 (m, 6H, 2 CH₃).

[0329] b) To [4-TBDMS-1-(toluene-4-sulfonyl)-butyl]-isocyanid (2.5 g,7.0 mmol) was added THF (25 ml), propionaldehyde (450 mg, 7.7 mmol) andKOtBu (250 mg) at room temperature (reaction slightly exothermic). Thereaction mixture was stirred for 20 minutes at room temperature, thesolvent was removed and the residue dissolved in saturated methanolicammonia (25 ml) and heated at 100° for 5 hours in a sealed tube. Aftercooling to room temperature the solvent was removed and the residuechromatographed on SiO₂ with a gradient from EtOAc to EtOAc and Ethanol(7:3) yielding example 8 (550 mg, 29.1%) as a slighly yellow oil.

[0330]¹H-NMR (300 MHz, CDCl₃): 7.53 (s, 1H, H-C2); ˜6.6 (br.s, NH); 3.65(t, J=˜6.0, 2H, OCH₂); 2.66 (t, J=7.1, 2H, CH₂-C4); 2.57 (qa, J=7.5, 2H,CH₂-C5); 1.81 (m, 2H, CH₂); 1.21 (t, J=7.5, 3H, CH₃); 0.90 (s, 9H, tBu);0.06 (s, 6H, 2 CH₃).

Example 9 2-(N-Trityl-5-ethyl-1H-imidazol-4-yl)-propanol

[0331]

[0332] a) To a solution of5-Ethyl-4-(3-tert-butyldimethylsilanyloxy-propyl)-1H-imidazole (1,96mmol, 500 mg) in acetonitrile (5 ml) were added triethylamine (550 μl,3.9 mmol) and a solution of tritylchloride (820 mg, 3 mmol) inacetonitrile (10 ml). The resulting mixture was stirred at 20° C.overnight. The mixture was concentrated under reduced pressure and theresidue redissolved in ethylacetate, washed with water (2×) and brine(1×) and concentrated under reduced pressure.

[0333] b) To a stirred solution of the tritylated product in THF (20 ml)was added at room temperature TBAF×3H₂O (800 mg, 2.5 mmol). After 1.5and 4.5 hours another two portions of TBAF×3H₂O (400 mg, 1.3 mmol) wereadded and the reaction mixture was stirred for 5.5 hours and evaporated.The residue was chromatographed on SiO₂ (deactivated with Et₃N) with agradient of EtOAc/hexane (1:1) to EtOAc yielding2-(N-trityl-5-ethyl-1H-imidazol-4-yl)-propanol (653 mg, 87%) ascolorless powder.

[0334]¹H-NMR (300 MHz, DMSO-d6, ratio of isomers ˜1:1): 7.41-7.30 (m,2×9 arom. H); 7.07-7.05 (m, 2×6 arom. H); 6.97 and 6.96 (2s, 2H, H-C2,two isomers); 4.45 and 4.11 (2t, J=5.0 and 4.9, 2×1H, OH, two isomers);3.41 and 2.75 (2td, ˜qa, J˜6.2, 5.1 and 5.9, 5.1, 2×2H, OCH₂, twoisomers); 2.42-2.34 and 2.06-1.98 (2m, 2×4H, CH₂); 1.72 (m, 2H, CH₂);1.12 (t, J=7.5, 3H, CH₃); 0.44-0.37 (m, 2H, CH₂); 0.02 (t, J=7.3, 3H,CH₃).

Example 105-Isopropyl-4-(3-tert-butyldimethylsilanyloxy-propyl)-1H-imidazole

[0335]

[0336]5-Isopropyl-4-(3-tert-butyldimethylsilanyloxy-propyl)-1H-imidazole wasprepared using the procedure described for example 8a. The subsequenttransformation to the imidazole was carried out according to example 8busing isobutyraldehyde.

[0337]¹H-NMR (300 MHz, CDCl₃): 7.62 (s, 1H, H-C2); ˜6.5 (br.s, NH); 3.64(t, J=5.9, 2H, OCH₂); 3.00 (sp, J˜6.9, 1H, CH-C5); 2.67 (t, J=7.2, 2H,CH₂-C4); 1.81 (m, 2H, CH₂); 1.26 (d, J=7.0, 6H, 2 CH₃); 0.90 (s, 9H,tBu); 0.06 (s, 6H, 2 CH₃).

Example 11 2-(N-Trityl-5-isopropyl-1H-imidazol-4-yl)-propanol

[0338]

[0339] Tritylation of the imidazole ring and removal of the TBDMSprotection group has been carried out using the procedure described inexample 9.

[0340]¹H-NMR (300 MHz, DMSO-d6): 7.41-7.29 (m, 9 arom. H); 7.07-7.04 (m,6 arom. H); 6.96 (s, H-C2); 4.10 (t, J=4.9, 1H, OH); 2.78-2.71 (m, 3H,OCH₂, CH-C5); 2.06-1.97 (m, 2H, CH₂); 1.13 (d, J=6.8, 6H, CH₃);0.40-0.34 (m, 2H, CH₂).

Example 125-Phenyl-4-(3-tert-butyldimethylsilanyloxy-propyl)-1H-imidazole

[0341]

[0342] a) Preparation of the proyplated Tosmic intermediate has beencarried out according to example 8.

[0343] b) To a stirred solution of this intermediate (4.54 g, 12.8 mmol)in saturated methanolic ammonia (50 ml) was added benzaldehyde (1.41 ml,14.1 ml) at room temperature. After stirring for 10 minutes at roomtemperature the reaction mixture was heated for 15 hours at 100° C.,cooled to room temperature and evaporated. The residue waschromatographed on SiO₂ with a gradient of CHCl₃ to CHCl₃/EtOH (9:1)yielding example 12 (1.78 g, 44%) as a slightly yellow oil.

[0344]¹H-NMR (300 MHz, CDCl₃): 7.75 (s, 1H, H-C5); 7.61-7.29 (m, 5 arom.H, NH); 3.72 (t, J=5.7, 2H, OCH₂); 2.95 (t, J=7.1, 2H, CH₂-C4); 1.93(tt, 2H, CH₂); 0.92 (s, 9H, tBu); 0.08 (s, 6H, 2 CH₃).

Example 13 2-(N-Trityl-5-phenyl-1H-imidazol-4-yl)-propanol

[0345]

[0346] Tritylation of the imidazole ring and removal of the TBDMSprotection group has been carried out using the procedure described inexample 9.

[0347]¹H-NMR (300 MHz, DMSO-d6): 7.75-7.72 (m, 2 arom. H); 7.46-7.31 (m,11 arom. H); 7.22-7.15 (m, 8 arom. H); 4.14 (t, J=4.9, 1H, OH); 2.73(dt, ˜qa, J˜6.0, 2H, OCH₂); 2.42 (m, 2H, CH₂); 0.39 (m, 2H, CH₂-C4).

Examples 14/1-14/6

[0348]

[0349] The following general procedure was applied for the mesylation ofexamples 1, 5, 7, 9, 11, 13:

[0350] To a stirred solution of one of the alcohols 1, 5, 7, 9, 11 or 13(10.8 mmol) in CH₂Cl₂ (40 ml) was added at 4° C. Et₃N (2.72 g, 26.9mmol) and slowly a solution of methanesufonylchloride (1.08 ml, 14.0mmol) in CH₂Cl₂ (10 ml). The reaction mixture was stirred for 1 hour at4° C. and poured onto H₂O (100 ml) and EtOAc (150 ml). The organic phasewas extracted with saturated NaHCO₃-solution and saturated brine, dried(Na₂SO₄), the solvents were evaporated and the residue dried at highvacuum yielding the corresponding mesylates usually as amorphous solidswhich were not further purified.

Examples 15/1-15/13 Standard procedure for the arylether products

[0351]

[0352] To a stirred solution of an appropriate phenol (1.3 mmol) in DMSO(2 ml) a NaH-dispersion (1.5 mmol) was added at room temperature (H₂evolution). The reaction mixture was stirred for 30 minutes at roomtemperature followed by addition of mesylates 14/1-14/6 (1.0 mmol) inDMSO (1 ml) and stirring at 70° C. for 1-3 hours. After addition of H₂Oand EtOAc the organic layer was dried (MgSO₄) and the solvents wereevaporated. The residue was chromatographed using gradients of EtOAc andhexane and the product dissolved in EtOH (2 ml) and 2N aqueousHCl-solution (4 ml) was added followed by heating the reaction mixturefor 2-4 hours (TrOH usually precipitates during the course of thereaction). After cooling to room temperature the suspension wasfiltered, the filtrate evaporated to dryness and the residue extractedwith 10% aqueous Na₂CO₃-solution and CHCl₃. The organic fraction wasevaporated and the residue chromatographed on SiO₂ using a gradient ofCHCl₃ to CHCl₃/MeOH (5:1) yielding the products usually as amorphoussolids. exam- ple structure Name 15/1

4-[2-(4-Iodo- phenoxy)-ethyl]-5- methyl-1H- imidazole

[0353] Example 15/1 has been prepared starting from example 14/3 and4-iodophenol.

[0354] Mass Spectrometry: [M+H]⁺ 329

[0355] Mass Spectrometry: [M−H]⁻ 327

[0356] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,37

[0357] MP: 160° C. exam- ple structure Name 15/2

Cyclopropyl- {4-[2-(5- methyl-1H- imidazol-4- yl)-ethoxy]- phenyl}-methanone

[0358] Example 15/2 has been prepared starting from example 14/3 andcyclopropyl-(4-hydroxy-phenyl)-methanone.

[0359] Mass Spectrometry: [M+H]⁺ 271

[0360] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,34

[0361] MP: 163° C. exam- ple structure Name 15/3

4-[4-(4-Iodo- phenoxy)- butyl]-5- methyl-1H- imidazole

[0362] Example 15/3 has been prepared starting from example 14/2 and4-iodophenol.

[0363] Mass Spectrometry: [M+H]⁺357

[0364] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,46

[0365] MP: 125° C. example structure Name 15/4

Cyclopropyl-{4-[4-(5-methyl-1H-imidazol-4- yl)-butoxy]-phenyl}-methanone

[0366] Example 15/4 has been prepared starting from example 14/2 andcyclopropyl-(4-hydroxy-phenyl)-methanone.

[0367] Mass Spectrometry: [M+H]⁺ 299

[0368] Mass Spectrometry: [M−H]⁻ 297

[0369] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,34 ex- am-ple structure Name 15/5

5-Methyl-4- [4-(naphtha- len-2-yloxy)- butyl]-1H- imidazole

[0370] Example 15/5 has been prepared starting from example 14/2 and2-naphthol.

[0371] Mass Spectrometry: [M+H]⁺ 281

[0372] Mass Spectrometry: [M−H]⁻ 279

[0373] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,41

[0374] MP: 85° C. exam- ple structure Name 15/6

4-[4-(Biphenyl-4-yloxy)-butyl]-5-methyl-1H- imidazole

[0375] Example 15/6 has been prepared starting from example 14/2 and4-phenylphenol.

[0376] Mass Spectrometry: [M+H]⁺ 308

[0377] Mass Spectrometry: [M−H]⁻ 306

[0378] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,39

[0379] MP: 136° C. exam- ple structure Name 15/7

5-Ethyl-4-[3-(4-iodo-phen- oxy)-propyl]-1H-imidazole

[0380] Example 15/7 has been prepared starting from example 14/4 and4-iodophenol.

[0381] Mass Spectrometry: [M+H]⁺ 357

[0382] Mass Spectrometry: [M−H]⁻ 356

[0383] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,56

[0384] MP: 91° C. exam- ple structure Name 15/8

Cyclopropyl-{4-[3- (5-ethyl-1H- imidazol-4-yl)- propoxy]-phenyl}-methanone

[0385] Example 15/8 has been prepared starting from example 14/4 andcyclopropyl-(4-hydroxy-phenyl)-methanone.

[0386] Mass Spectrometry: [M+H]⁺ 300

[0387] Mass Spectrometry: [M−H]⁻ 298

[0388] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,56

[0389] MP: 115° C. exam- ple structure Name 15/9

5-Ethyl-4-[3-(naphthalen-2- yloxy)-propyl]-1H- imidazole

[0390] Example 15/9 has been prepared starting from example 14/4 and2-naphthol.

[0391] Mass Spectrometry: [M+H]⁺ 281

[0392] Mass Spectrometry: [M−H]⁻ 280

[0393] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,57

[0394] MP: 92° C. exam- ple Structure Name 15/10

4-[3-(4-Iodo-phenoxy)- propyl]-5-isopropyl-1H- imidazole

[0395] Example 15/10 has been prepared starting from example 14/5 and4-iodophenol.

[0396] Mass Spectrometry: [M+H]⁺ 371

[0397] Mass Spectrometry: [M−H]⁻ 369

[0398] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,56

[0399] MP: 111° C. exam- ple Structure Name 15/11

Cyclopropyl-{4-[3- (5-isopropyl-1H- imidazol-4-yl)- propoxy]-phenyl}-methanone

[0400] Example 15/11 has been prepared starting from example 14/5 andcyclopropyl-(4-hydroxy-phenyl)-methanone.

[0401] Mass Spectrometry: [M+H]⁺ 313

[0402] Mass Spectrometry: [M−H]⁻ 311

[0403] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,55

[0404] MP: 143° C. exam- ple Structure Name 15/12

4-[3-(4-Iodo-phenoxy)- propyl]-5-phenyl-1H- imidazole

[0405] Example 15/12 has been prepared starting from example 14/6 and4-iodophenol.

[0406] Mass Spectrometry: [M+H]⁺ 405

[0407] Mass Spectrometry: [M−H]⁻ 403

[0408] MP: 118° C. exam- ple structure Name 15/13

Cyclopropyl-{4- [3-(5-phenyl-1H- imidazol-4-yl)- propoxy]- phenyl}-methanone

[0409] Example 15/13 has been prepared starting from example 14/6 andcyclopropyl-(4-hydroxy-phenyl)-methanone.

[0410] Mass Spectrometry: [M+H]⁺ 347

[0411] Mass Spectrometry: [M−H]⁻ 346

[0412] TLC (solvent: DCM:MeOH=95:5, Polygram ALOX) R_(f): 0,50

[0413] MP: 154° C.

Examples 16/1-16/47 Standard procedure for the benzylether products

[0414]

[0415] To a stirred solution of one of the alcohols 1, 5, 7, 9, 11 or 13(1.0 mmol) in THF (3 ml) was added NaH-dispersion (2.0 mmol) and15-crown-5 (10 μl) at room temperature (H₂ evolution). The reactionmixture was stirred for 30 minutes and cooled to 4° C. followed byaddition of the appropriate benzylhalide(1.1 mmol) and stirring at roomtemperature (gentle heating if required) for 1-24 hours. After additionof H₂O and EtOAc the organic layer was dried (MgSO₄) and the solventswere evaporated.

[0416] The residue was chromatographed using gradients of EtOAc andhexane and the product dissolved in EtOH (2 ml) and 2N aqueousHCl-solution (4 ml) was added followed by heating the reaction mixturefor 2-4 hours (TrOH usually precipitates during the course of thereaction). After cooling to room temperature the suspension wasfiltered, the filtrate extracted with 10% aqueous Na₂CO₃-solution andCHCl₃. The organic fraction was evaporated and the residuechromatographed on SiO₂ using a gradient of CHCl₃ to CHCl₃/MeOH (5:1)yielding the products usually as amorphous solids. exam- ple StructureName 16/1

4-(3-Benzyloxy- propyl)-5-methyl- 1H-imidazole

[0417] Example 16/1 has been prepared starting from example 1 andbenzylbromide.

[0418] Mass Spectrometry: [M+H]⁺ 231

[0419] Mass Spectrometry: [M−H]⁻ 229

[0420]¹H-NMR (300 MHz, CDCl₃): 1.88 (p, 2H); 2.15 (s, 3H); 2.64 (t, 2H);3.51 (t, 2H); 4.50 (s, 2H); 7.24-7.39 (m, 6H).

[0421] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,38 exam- pleStructure Name 16/2

4-[3-(4-Iodo- benzyloxy)- propyl]-5- methyl-1H- imidazole

[0422] Example 16/2 has been prepared starting from example 1 and4-iodobenzylbromide.

[0423] Mass Spectrometry: [M+H]⁺ 357

[0424] Mass Spectrometry: [M−H]⁻ 355

[0425] TLC (solvent: DCM/MeOH95:5, Polygram ALOX) R_(f): 0,37 exam- plestructure Name 16/3

Cyclopropyl-{4-[3-(5-methyl-1H-imidazol-4-yl)-propoxymethyl]-phenyl}-methanone

[0426] Example 16/3 has been prepared starting from example 1 andp-cyclopropyl-carbonyl-benzylbromid.

[0427] Mass Spectrometry: [M+H]⁺ 300

[0428] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,35 exam- plestructure Name 16/4

5-Methyl-4-[3-(4-trifluoromethoxy- benzyloxy)-propyl]-1H-imidazole

[0429] Example 16/4 has been prepared starting from example 1 and4-(trifluormethoxy)-benzylbromid.

[0430] Mass Spectrometry: [M−H]⁻ 313

[0431] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,41 exampleStructure Name 16/5

5-Methyl-4-[3-(naphthalen-2-ylmethoxy)- propyl]-1H-imidazole

[0432] Example 16/5 has been prepared starting from example 1 and2-(bromomethyl)-naphthalene.

[0433] Mass Spectrometry: [M+H]⁺ 281

[0434] Mass Spectrometry: [M−H]⁻ 280

[0435] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,55 examplestructure Name 16/6

4-[3-(Biphenyl-4-ylmethoxy)-propyl]-5- methyl-1H-imidazole

[0436] Example 16/6 has been prepared starting from example 1 and4-bromomethylbiphenyl.

[0437] Mass Spectrometry: [M+H]⁺ 307

[0438] Mass Spectrometry: [M−H]⁻ 305

[0439] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,58

[0440] MP: 95° C. exam- ple structure Name 16/7

5-Methyl-4-[3- (naphthalen-1- ylmethoxy)- propyl]-1H- imidazole

[0441] Example 16/7 has been prepared starting from example 1 and1-(chloromethyl)-naphthalene.

[0442] Mass Spectrometry: [M+H]⁺ 281

[0443] Mass Spectrometry: [M−H]⁻ 280

[0444] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,54 exam- plestructure Name 16/8

4-[3-(4-tert-Butyl- benzyloxy)-propyl]- 5-methyl-1H- imidazole

[0445] Example 16/8 has been prepared starting from example 1 and4-(tert-butyl)benzyl bromide.

[0446] Mass Spectrometry: [M+H]⁺ 288

[0447]¹H-NMR (300 MHz, CDCl₃): 1.32 (s, 9H); 1.88 (p, 2H); 2.15 (s, 3H);2.65 (t, 2H); 3.50 (t, 2H); 4.49 (s, 2H); 7.22-7.44 (m, 3H).

[0448] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,48 exam- plestructure Name 16/9

5-Methyl-4-[3-(4- trifluoromethyl- benzyloxy)-propyl]- 1H-imidazole

[0449] Example 16/9 has been prepared starting from example 1 and4-(trifluoromethyl)-benzylbromide.

[0450] Mass Spectrometry: [M+H]⁺ 299

[0451] Mass Spectrometry: [M−H]⁻ 297

[0452]¹H-NMR (300 MHz, CDCl₃): 1.92 (p, 2H); 2.20 (s, 3H); 2.67 (t, 2H);3.53 (t, 2H); 4.47 (s, 2H); 7.41-7.45 (m, 3H); 7.60 (d, 2H).

[0453] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,48 exam- plestructure Name 16/10

4-[3-(5-Methyl-1H-imidazol- 4-yl)-propoxymethyl]- benzonitrile

[0454] Example 16/10 has been prepared starting from example 1 and4-cyanobenzylbromide.

[0455] Mass Spectrometry: [M+H]⁺ 256

[0456] Mass Spectrometry: [M−H]⁻ 254

[0457] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,46 exam- plestructure Name 16/11

4-[3-(3,5-Dichloro-benzyloxy)- propyl]-5-methyl-1H-imidazole

[0458] Example 16/11 has been prepared starting from example 1 and3,5-dichlorobenzylchoride.

[0459] Mass Spectrometry: [M+H]⁺ 299

[0460] Mass Spectrometry: [M−H]⁺ 297

[0461]¹H-NMR (300 MHz, CDCl₃): 1.92 (p, 2H); 2.18 (s, 3H); 2.64 (t, 2H);3.50 (t, 2H); 4.43 (s, 2H); 7.20 (s, 2H); 7.26 (s, 1H); 7.44 (s, 1H).

[0462] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,52 exam- plestructure Name 16/12

5-Methyl-4-[3-(3- phenoxy-benzyloxy)- propyl]-1H- imidazole

[0463] Example 16/12 has been prepared starting from example 1 and3-phenoxy-benzyl-chloride.

[0464] Mass Spectrometry: [M+H]⁺ 323

[0465] Mass Spectrometry: [M−H]⁻ 322

[0466] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,54 exam- plestructure Name 16/13

4-[3-(3,5-Bis-trifluoromethyl- benzyloxy)-propyl]-5-methyl- 1H-imidazole

[0467] Example 16/13 has been prepared starting from example 1 and3,5-bis(trifluoromethyl)-benzylbromide.

[0468] Mass Spectrometry: [M+H]⁺ 367

[0469] Mass Spectrometry: [M−H]⁻ 365

[0470] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,62

[0471] MP: 90° C. exam- ple structure Name 16/14

4-[3-(3-Iodo- benzyloxy)- propyl]-5- methyl-1H- imidazole

[0472] Example 16/14 has been prepared starting from example 1 and3-iodobenzylbromide.

[0473] Mass Spectrometry: [M+H]⁺ 357

[0474]¹H-NMR (300 MHz, CDCl₃): 1.91 (p, 2H); 2.16 (s, 3H); 2.65 (t, 2H);3.50 (t, 2H); 4.43 (s, 2H); 7.08 (t, 1H); 7.22-7.43 (m, 2H); 7.62 (d,1H); 7.69 (s, 1H).

[0475] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,61 exam- pleStructure Name 16/15

4-[3-(Biphenyl- 2-ylmethoxy)- propyl]-5- methyl-1H- imidazole

[0476] Example 16/15 has been prepared starting from example 1 and2-phenylbenzylbromide.

[0477] Mass Spectrometry: [M+H]⁺ 307

[0478] Mass Spectrometry: [M−H]⁻ 305

[0479] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,61 exam- pleStructure Name 16/16

5-Methyl-4-[3-(3-trifluoromethyl- benzyloxy)-propyl]-1H-imidazole

[0480] Example 16/16 has been prepared starting from example 1 and3-(trifluoromethyl)-benzylbromide.

[0481] Mass Spectrometry: [M+H]⁺ 299

[0482] Mass Spectrometry: [M−H]⁻ 297 exam- ple structure Name 16/17

4-[2-(4-Iodo-benzyloxy)- ethyl]-5-methyl-1H- imidazole

[0483] Example 16/17 has been prepared starting from example 7 and4-iodobenzylbromide.

[0484] Mass Spectrometry: [M+H]⁺ 343

[0485] Mass Spectrometry: [M−H]⁻ 341

[0486] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,64

[0487] MP: 74° C. exam- ple structure Name 16/18

5-Methyl-4-[2-(4-tri- fluoromethoxy-benzyloxy)- ethyl]-1H-imidazole

[0488] Example 16/18 has been prepared starting from example 7 and4-(trifluormethoxy)-benzylbromide.

[0489] Mass Spectrometry: [M+H]⁺ 301

[0490] Mass Spectrometry: [M−H]⁻ 300

[0491] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,65

[0492] MP: 66° C. exam- ple structure Name 16/19

4-[4-(4-Iodo-ben- zyloxy)-butyl]-5- methyl-1H- imidazole

[0493] Example 16/19 has been prepared starting from example 5 and and4-iodobenzylbromide.

[0494] Mass Spectrometry: [M+H]⁺ 371

[0495] Mass Spectrometry: [M−H]⁻ 369

[0496] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,62 exam- plestructure Name 16/20

Cyclopropyl- {4-[4-(5-meth- yl-1H-imida- zol-4-yl)-bu- toxymethyl]-phenyl}- methanone

[0497] Example 16/20 has been prepared starting from example 5 andp-cyclopropyl-carbonyl-benzylbromide.

[0498] Mass Spectrometry: [M+H]⁺ 313

[0499] Mass Spectrometry: [M−H]⁻ 311

[0500] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,62 exam- plestructure Name 16/21

5-Methyl-4-[4- (4-trifluorometh- oxy-benzyloxy)- butyl]-1H- imidazole

[0501] Example 16/21 has been prepared starting from example 5 and4-(trifluormethoxy)-benzylbromide.

[0502] Mass Spectrometry: [M+H]⁺ 329

[0503] Mass Spectrometry: [M−H]⁻ 327

[0504] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,55 exam- plestructure Name 16/22

4-[3-(5-Methyl- 1H-imidazol- 4-yl)-propoxy- methyl]- pyridine

[0505] Example 16/22 has been prepared starting from example 1 and4-(bromomethyl)pyridine.

[0506] Mass Spectrometry: [M+H]⁺ 232

[0507]¹H-NMR (300 MHz, CDCl₃): 1.92 (p, 2H); 2.17 (s, 3H); 2.65 (t, 2H);3.53 (t, 2H); 4.48 (s, 2H); 7.24 (d, 2H); 7.42 (s, 1H); 8.56 (d, 2H).

[0508] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,44 examplestructure Name 16/23

5-Methyl-4-[2-(naphthalen-2-ylmethoxy)- ethyl]-1H-imidazole

[0509] Example 16/23 has been prepared starting from example 7 and2-(bromomethyl)-naphthalene.

[0510] Mass Spectrometry: [M+H]⁺ 267

[0511] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,57

[0512] MP: 88° C. example structure Name 16/24

4-[2-(Biphenyl-4-ylmethoxy)-ethyl]-5-methyl- 1H-imidazole

[0513] Example 16/24 has been prepared starting from example 7 and4-bromomethylbiphenyl.

[0514] Mass Spectrometry: [M+H]⁺ 293

[0515] Mass Spectrometry: [M−H]⁻ 291

[0516] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,56

[0517] MP: 109° C. example structure Name 16/25

4-[3-(3,5-Dimethyl-benzyloxy)-propyl]-5- methyl-1H-imidazole

[0518] Example 16/25 has been prepared starting from example 1 and3,5-dimethylbenzyl-bromide.

[0519] Mass Spectrometry: [M+H]⁺ 259

[0520]¹H-NMR (300 MHz, CDCl₃): 1.89 (p, 2H); 2.17 (s, 3H); 2.31 (s, 6H);2.64 (t, 2H); 3.53 (t, 2H); 4.46 (s, 2H); 6.96 (m, 3H); 7.32 (s, 1H).

[0521] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,48 examplestructure Name 16/26

5-Methyl-4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylmethoxy)-propyl]- 1H-imidazole

[0522] Example 16/26 has been prepared starting from example 1 and6-bromomethyl-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene.

[0523] Mass Spectrometry: [M+H]⁺ 341

[0524] Mass Spectrometry: [M−H]⁻ 339

[0525] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,56 ex- amplestructure Name 16/27

2-(4-Chloro-phenyl)-4-[3-(5-methyl-1H-imida-zol-4-yl)-propoxymethyl]-thiazole

[0526] Example 16/27 has been prepared starting from example 1 and4-(chlorormethyl)-2-(4-chlororphenyl)thiazole.

[0527] Mass Spectrometry: [M+H]⁺ 384

[0528]¹H-NMR (300 MHz, CDCl₃): 1.89 (p, 2H); 2.16 (s, 3H); 2.73 (t, 2H);3.56 (t, 2H); 4.62 (s, 2H); 7.22 (s, 1H); 7.30 (s, 1H); 7.41 (d, 2H);7.87 (d, 2H).

[0529] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,56

[0530] MP: 128° C. ex- ample Structure Name 16/28

5-tert-Butyl-3-[3-(5-methyl-1H-imidazol-4-yl)-pro-poxymethyl]-[1,2,4]oxadiazole

[0531] Example 16/28 has been prepared starting from example 1 and5-(tert-butyl)-3-(chloromethyl)-1,2,4-oxadiazole.

[0532] Mass Spectrometry: [M+H]⁺ 280

[0533]¹H-NMR (300 MHz, CDCl₃): 1.45 (s, 9H); 1.88 (p, 2H); 2.17 (s, 3H);2.70 (t, 2H); 3.60 (t, 2H); 4.61 (s, 2H); 7.44 (s, 1H). ex- ampleStructure Name 16/29

4-[2-(3-Iodo-benzyloxy)-ethyl]-5-methyl-1H-imidazole

[0534] Example 16/29 has been prepared starting from example 7 and3-iodobenzylbromide.

[0535] Mass Spectrometry: [M+H]⁺ 343

[0536] Mass Spectrometry: [M−H]⁻ 341

[0537] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,51 ex- amplestructure Name 16/30

4-[2-(4-Fluoro-benzyloxy)-ethyl]-5-methyl-1H-imidazole

[0538] Example 16/30 has been prepared starting from example 7 and4-fluorobenzylbromide.

[0539] Mass Spectrometry: [M+H]⁺ 235

[0540] Mass Spectrometry: [M−H]⁻ 233

[0541] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,49

[0542] MP: 55° C. ex- ample structure Name 16/31

5-Methyl-4-[4-(naphthalen-2-ylmethoxy)-butyl]-1H-imidazole

[0543] Example 16/31 has been prepared starting from example 5 and2-(bromomethyl)-naphthalene.

[0544] Mass Spectrometry: [M+H]⁺ 296

[0545] Mass Spectrometry: [M−H]⁻ 294

[0546] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,46 ex- amplestructure Name 16/32

5-Ethyl-4-[3-(4-trifluoromethoxy-benzyloxy)-propyl]-1H-imidazole

[0547] Example 16/32 has been prepared starting from example 9 and4-(trifluormethoxy)-benzylbromide.

[0548] Mass Spectrometry: [M+H]⁺ 329

[0549] Mass Spectrometry: [M−H]⁻ 327

[0550] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,57 ex- amplestructure Name 16/33

5-Ethyl-4-[3-(4-iodo-benzyloxy)-propyl]-1H-imidazole

[0551] Example 16/33 has been prepared starting from example 9 and and4-iodobenzylbromide.

[0552] Mass Spectrometry: [M+H]⁺ 371

[0553] Mass Spectrometry: [M−H]⁻ 369

[0554] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,54 ex- amplestructure Name 16/34

Cyclopropyl-{4-[3-(5-ethyl-1H-imidazol-4-yl)-pro-poxymethyl]-phenyl}-methanone

[0555] Example 16/34 has been prepared starting from example 9 andp-cyclopropyl-carbonyl-benzylbromide.

[0556] Mass Spectrometry: [M+H]⁺ 313

[0557] Mass Spectrometry: [M−H]⁻ 311

[0558] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,56

[0559] MP: 93° C. ex- ample structure Name 16/35

4-[3-(Biphenyl-4-ylmethoxy)-propyl]-5-ethyl-1H-imidazole

[0560] Example 16/35 has been prepared starting from example 9 and4-bromomethylbiphenyl.

[0561] Mass Spectrometry: [M+H]⁺ 322

[0562] Mass Spectrometry: [M−H]⁻ 319

[0563] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,56

[0564] MP: 123° C. ex- ample structure Name 16/36

5-Ethyl-4-[3-(naphthalen-2-ylmethoxy)-propyl]-1H-imidazole

[0565] Example 16/36 has been prepared starting from example 9 and2-(bromomethyl)-naphthalene.

[0566] Mass Spectrometry: [M+H]⁺ 295

[0567] Mass Spectrometry: [M−H]⁻ 294

[0568] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,58

[0569] MP: pb 78° C. ex- ample structure Name 16/37

5-Iospropyl-4-[3-(4-trifluoromethoxy-benzyloxy)-propyl]-1H-imidazole

[0570] Example 16/37 has been prepared starting from example 11 and4-(trifluormethoxy)-benzylbromide.

[0571] Mass Spectrometry: [M+H]⁺ 343

[0572] Mass Spectrometry: [M−H]⁻ 341

[0573] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,58 ex- amplestructure Name 16/38

4-[3-(4-Iodo-benzyloxy)-propyl]-5-isopropyl-1H-imidazole

[0574] Example 16/38 has been prepared starting from example 11 and and4-iodobenzyl-bromide.

[0575] Mass Spectrometry: [M+H]⁺ 385

[0576] Mass Spectrometry: [M−H]⁻ 383 ex- ample structure Name 16/39

Cyclopropyl-{4-[3-(5-isopropyl-1H-imidazol-4-yl)-propoxy-methyl]-phenyl}-methanone

[0577] Example 16/39 has been prepared starting from example 11 andp-cyclopropyl-carbonyl-benzylbromide.

[0578] Mass Spectrometry: [M+H]⁺ 327

[0579] Mass Spectrometry: [M−H]⁻ 326

[0580] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,53 ex- amplestructure Name 16/40

4-[3-(Biphenyl-4-ylmethoxy)-propyl]-5-isopropyl-1H-imidazole

[0581] Example 16/40 has been prepared starting from example 11 and4-bromomethylbiphenyl.

[0582] Mass Spectrometry: [M+H]⁺ 335

[0583] Mass Spectrometry: [M−H]⁻ 333

[0584] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,54 ex- amplestructure Name 16/41

5-Isopropyl-4-[3-(naphthalen-2-ylmethoxy)-propyl]-1H-imidazole

[0585] Example 16/41 has been prepared starting from example 11 and2-(bromomethyl)-naphthalene.

[0586] Mass Spectrometry: [M+H]⁺ 309

[0587] Mass Spectrometry: [M−H]⁻ 307

[0588] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,55

[0589] MP: 106° C. ex- ample structure Name 16/42

4-[3-(3-Iodo-benzyloxy)-propyl]-5-isopropyl-1H-imidazole

[0590] Example 16/42 has been prepared starting from example 11 and3-iodobenzylbromide.

[0591] Mass Spectrometry: [M+H]⁺ 385

[0592] Mass Spectrometry: [M−H]⁻ 383

[0593] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,48 ex- amplestructure Name 16/43

5-Phenyl-4-[3-(4-trifluoromethoxy-benzyloxy)-propyl]-1H-imidazole

[0594] Example 16/43 has been prepared starting from example 13 and4-(trifluormethoxy)-benzylbromide.

[0595] Mass Spectrometry: [M+H]⁺ 377

[0596] Mass Spectrometry: [M−H]⁻ 375

[0597] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,61

[0598] MP: 105° C. ex- ample structure Name 16/44

4-[3-(4-Iodo-benzyloxy)-propyl]-5-phenyl-1H-imidazole

[0599] Example 16/44 has been prepared starting from example 13 and4-iodobenzylbromide.

[0600] Mass Spectrometry: [M+H]⁺ 419

[0601] Mass Spectrometry: [M−H]⁻ 417

[0602] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,70

[0603] MP: 64° C. ex- ample Structure Name 16/45

4-[3-(Biphenyl-4-ylmethoxy)-propyl]-5-phenyl-1H-imidazole

[0604] Example 16/45 has been prepared starting from example 13 and4-bromomethylbiphenyl.

[0605] Mass Spectrometry: [M+H]⁺ 369

[0606] Mass Spectrometry: [M−H]⁻ 367

[0607] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,59

[0608] MP: 133° C. ex- ample Structure Name 16/46

4-[3-(Naphthalen-2-ylmethoxy)-propyl]-5-phenyl-1H-imidazole

[0609] Example 16/46 has been prepared starting from example 13 and2-(bromomethyl)-naphthalene.

[0610] Mass Spectrometry: [M+H]⁺ 343

[0611] Mass Spectrometry: [M−H]⁻ 341

[0612] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,59

[0613] MP: 112° C. ex- ample structure Name 16/47

4-[3-(3-Iodo-benzyloxy)-propyl]-5-phenyl-1H-imidazole

[0614] Example 16/47 has been prepared starting from example 13 and3-iodobenzylbromide.

[0615] Mass Spectrometry: [M+H]⁺ 419

[0616] Mass Spectrometry: [M−H]⁻ 417

[0617] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,58

[0618] MP: 67° C.

Example 17 1-{4-[3-(5-Methyl-1H-imidazol-4-yl)-propoxy]-phenyl}-ethanoneoxime

[0619] To a mixtures of 1 mmol of example 3/3, 750 mg pyridine and 25 mlethanol 650 mg hydroxylamine hydrochlorid were added. The mixture wasstirred and refluxed for three hours. After removal of the solventsunder reduced pressure, H₂O and EtOAc were added. The crude product wasextracted and the organic layer was dried (MgSO₄) before evaporation ofthe solvent. The residue was chromatographed on SiO₂ using a gradient ofCHCl₃ to CHCl₃/MeOH (5:1) yielding the product as solids. ex- amplestructure Name 17

1-{4-[3-(5-Methyl-1H-imidazol-4-yl)-propoxy]-phenyl}-ethanone oxime

[0620] Mass Spectrometry: [M+H]⁺ 274

[0621] Mass Spectrometry: [M−H]⁻ 272

[0622]¹H-NMR (300 MHz, CDCl₃): 1.86-2.1 (m, 8H); 2.5-2.65 (m, 2H);3.85-3.94 (m, 2 H); 6.87-6.91 (d, 2 H); 7.51-7.53 (d, 2H); 7.32 (s, 1H); 10.95 (s, 1 H); 11.5-11.57 (d, 1H).

[0623] TLC (solvent: DCM/MeOH=95:5, Polygram ALOX) R_(f): 0,29

[0624] MP: 154° C.

Example 18 Tablet containing 50 mg of active substance

[0625] A typical tablet, which may be prepared by conventionaltabletting techniques, may contain:

[0626] Tablet containing 50 mg of active substance

[0627] Composition: (1) Active substance  50.0 mg (2) Lactose  98.0 mg(3) Maize starch  50.0 mg (4) Polyvinylpyrrolidone  15.0 mg (5)Magnesium stearate  2.0 mg 215.0 mg

[0628] Preparation:

[0629] (1), (2) and (3) are mixed together and granulated with anaqueous solution of (4). (5) is added to the dried granulated material.From this mixture tablets are pressed, biplanar, faceted on both sidesand with a dividing notch on one side.

[0630] Diameter of the tablets: 9 mm.

Example 19 Capsules containing 50 mg of active substance

[0631] A typical hard gelatine capsule, which may be prepared byconventional techniques, may contain:

[0632] Capsules containing 50 mg of active substance

[0633] Composition: (1) Active substance  50.0 mg (2) Dried maize starch 58.0 mg (3) Powdered lactose  50.0 mg (4) Magnesium stearate  2.0 mg160.0 mg

[0634] Preparation:

[0635] (1) is triturated with (3). This trituration is added to themixture of (2) and (4) with vigorous mixing.

[0636] This powder mixture is packed into size 3 hard gelatine capsulesin a capsule filling machine.

Example 20 Suppositories containing 150 mg of active substance:

[0637] Typical suppositories may contain:

[0638] Suppositories containing 150 mg of active substance:

[0639] 1 suppository contains: Active substance  150.0 mgPolyethylenglycol 1500  550.0 mg Polyethylenglycol 6000  460.0 mgPolyethylenesorbitan monostearate  840.0 mg 2000.0 mg

[0640] Preparation:

[0641] The polyethyleneglycol is melted together withpolyethylenesorbitan monostearate. The ground active substance ishomogeneously dispersed in the melt. This is then poured into slightlychilled suppository moulds.

Example 21 Dry ampoule containing 35 mg of active substance per 2 mlComposition

[0642] Typical dry ampoules may contain:

[0643] Dry ampoule containing 35 mg of active substance per 2 ml

[0644] Composition: Active substance  35.0 mg Mannitol 100.0 mg waterfor injections ad 2.0 ml

[0645] Preparation:

[0646] Active substance and mannitol are dissolved in water. Afterpackaging, the solution is freeze-dried.

[0647] To produce the solution ready for use, the product is dissolvedin water for injections.

1. A compound of formula (I):

wherein R¹ is a hydrogen atom or a functional group which can convert into a hydrogen atom in vivo, R² is a C₁₋₆-alkyl, C₃₋₇-cycloalkyl, aryl or aryl-C₁₋₂-alkyl group, n is 2,3,4or5, X is an oxygen or sulfur atom or a —CO—, —O—CH₂- or —SO—CH₂- group, Ar is a phenylene or naphthylene group, a 5-membered heteroarylene group linked via a carbon or nitrogen atom and containing an imino group optionally substituted by a C₁₋₄-alkyl or C₁₋₄-alkyl-carbonyl group, or an oxygen or sulfur atom, an imino group optionally substituted by a C₁₋₄-alkyl group, or an oxygen or sulfur atom, and additionally a nitrogen atom, an imino group optionally substituted by a C₁₋₄-alkyl group, and two nitrogen atoms or an oxygen or sulfur atom, and two nitrogen atoms, or a 6-membered heteroarylene group containing one or two nitrogen atoms, wherein the above-mentioned phenylene or 5- or 6-membered heteroarylene groups are optionally condensed via pairs of two adjacent carbon atoms with one or two saturated, unsaturated or aromatic carbocyclic or heterocyclic groups, each of which are optionally substituted by one or two carbonyl or C₁₋₃-alkyl groups, and the resulting condensed bi- or tricycles may be linked to X via the carbocyclic or heterocyclic moiety, and Y is a hydrogen, fluorine, chlorine, bromine or iodine atom, a hydroxy, cyano, C₁₋₆-alkyl, C₃₋₇-cycloalkyl, acetylene, C₁₋₄-alkyl-acetylene, C₁₋₄-alkyl-carbonyl, C₃₋₇-cycloalkyl-carbonyl, —C(═N—OH)-CH₃, phenyl, 5- or 6-membered heteroaryl, C₁₋₆-alkyloxy or phenyloxy group, wherein the phenyl rings contained in all the above definitions may additionally be substituted by one or two fluorine, chlorine, bromine or iodine atoms, or by one or two C₁₋₆-alkyl or C₁₋₆-alkoxy groups, wherein the substituents may be the same or different, and the hydrogen atoms of alkyl groups contained in all the above definitions may be partly or fully replaced by fluorine atoms, or a diastereomer, enantiomer, mixture or salt thereof.
 2. A compound of formula I according to claim 1, wherein R¹ is a hydrogen atom or a trityl group, R² is a C₁₋₄-alkyl, C₃₋₅-cycloalkyl or aryl group, n is 2, 3 or 4, X is an oxygen or sulfur atom or a —O—CH₂- or —SO—CH₂- group, Ar is a 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 2,5-naphthylene or 2,6-naphthylene group, a 5-membered heteroarylene group linked via a carbon or nitrogen atom and a carbon atom containing an imino group optionally substituted by a C₁₋₄-alkyl or C₁₋₄-alkyl-carbonyl group, or an oxygen or sulfur atom, an imino group optionally substituted by a C₁₋₄-alkyl group, or an oxygen or sulfur atom, and additionally a nitrogen atom, an imino group optionally substituted by a C₁₋₄-alkyl group, and two nitrogen atoms or an oxygen or sulfur atom, and two nitrogen atoms, or a 6-membered heteroarylene group containing one or two nitrogen atoms, wherein two adjacent carbon atoms of the above-mentioned phenylene or 5- or 6-membered heteroarylene groups are optionally bridged by a —CH₂—CH₂—CH₂—CH₂—, -(C═O)-CH₂—CH₂—CH₂—, —C(CH₃)₂-CH₂—CH₂—C(CH₃)₂-, —CH═CH—CH═N—, —O—CH₂—O— or —N═CH—S- group; and the resulting bicycles are linked to X via the carbocyclic moiety, and Y is a hydrogen, fluorine, chlorine, bromine or iodine atom, a hydroxy, cyano, C₁₋₄-alkyl, C₃₋₅-cycloalkyl, acetylene, C₁₋₄-alkyl-acetylene, C₁₋₄-alkyl-carbonyl, C₃₋₅-cycloalkyl-carbonyl, phenyl, —C(═N—OH)-CH₃, C₁₋₆-alkyloxy, phenyloxy group or a 5- or 6-membered heteroaryl group as defined above, wherein the phenyl rings contained in all the above definitions may additionally be substituted by one or two halogen atoms, C₁₋₆-alkyl or C₁₋₆-alkoxy groups while the substituents may be the same or different and the hydrogen atoms of alkyl groups contained in all the above definitions may be partly or fully replaced by fluorine atoms, or a diastereomer, enantiomer, mixture or salt thereof.
 3. A compound according to claim 2, wherein R¹, R², n, Ar and Y are as defined in claim 2 and X is an oxygen or sulfur atom or a —O—CH₂- group or a diastereomer, enantiomer, mixture, or salt thereof.
 4. A compound of formula I according to claim 1, wherein R¹ is a hydrogen atom, R² is a C₁₋₄-alkyl, C₃₋₅-cycloalkyl or phenyl group, n is 2, 3 or 4, X is an oxygen atom or a —O—CH₂- group, Ar is a group selected from the formulae

Y is a hydrogen, fluorine, chlorine, bromine or iodine atom, a hydroxy, cyano, C₁₋₄-alkyl, C₃₋₅-cycloalkyl, acetylene, C₁₋₄-alkyl-carbonyl, C₃₋₅-cycloalkyl-carbonyl, phenyl, —C(═N—OH)-CH₃, C₁₋₃-alkoxy, phenyloxy or imidazolyl group, wherein the phenyl rings contained in all the above definitions may additionally be substituted by a halogen atom, a C₁₋₃-alkyl or C₁₋₃-alkoxy group and the hydrogen atoms of alkyl groups contained in all the above definitions may be partly or fully replaced by fluorine atoms, or a diastereomer, enantiomer, mixture or salt thereof.
 5. A compound of formula I according to claim 4, wherein R¹ is a hydrogen atom, R² is a methyl, ethyl or isopropyl group, n is 2, 3 or 4, X is an oxygen atom or a —O—CH₂- group, Ar is a 1,3- or 1,4-phenylene or 2,5-naphthylene group and Y is a hydrogen, fluorine, chlorine, bromine or iodine atom, a hydroxy, cyano, C₁₋₄-alkyl, acetylene, C₁₋₄-alkyl-carbonyl, C₃₋₅-cycloalkyl-carbonyl, phenyl, C₁₋₃-alkoxy, phenoxy or imidazolyl group, wherein the phenyl rings contained in all the above definitions may additionally be substituted by a fluorine, chlorine, bromine or iodine atom atom, a C₁₋₃-alkyl or C₁₋₃-alkoxy group and the hydrogen atoms of alkyl groups contained in all the above definitions may be partly or fully replaced by fluorine atoms, or a diastereomer, enantiomer, mixture or salt thereof.
 6. A compound of formula I according to claim 5 wherein R² is a methyl group or a diastereomer, enantiomer, mixture or salt thereof.
 7. A compound of formula I according to claim 1 selected from the following compounds: (a) 5-Methyl-4-[4-(naphthalen-2-yloxy)-butyl]-1H-imidazole, (b) 4-[3-(4-Iodo-benzyloxy)-propyl]-5-methyl-1H-imidazole, (c) 5-Methyl-4-[3-(4-trifluoromethoxy-benzyloxy)-propyl]-1H-imidazole, (d) 5-Methyl-4-[3-(naphthalen-2-ylmethoxy)-propyl]-1H-imidazole, (e) 5-Methyl-4-[3-(4-trifluoromethyl-benzyloxy)-propyl]-1H-imidazole, (f) 4-[3-(3,5-Dichloro-benzyloxy)-propyl]-5-methyl-1H-imidazole, (g) 4-[3-(3,5-Bis-trifluoromethyl-benzyloxy)-propyl]-5-methyl-1H-imidazole, (h) 4-[3-(3-Iodo-benzyloxy)-propyl]-5-methyl-1H-imidazole, (i) 5-Methyl-4-[3-(3-trifluoromethyl-benzyloxy)-propyl]-1H-imidazole, (j) 4-[2-(4-Iodo-benzyloxy)-ethyl]-5-methyl-1H-imidazole, (k) 5-Methyl-4-[4-(4-trifluoromethoxy-benzyloxy)-butyl]-1H-imidazole and (l) 4-[3-(3,5-Dimethyl-benzyloxy)-propyl]-5-methyl-1H-imidazole, or a diastereomer, enantiomer, mixture or salt thereof.
 8. A pharmaceutically acceptable salt of a compound according to claim
 1. 9. A pharmaceutical composition comprising a compound according to claim
 1. 10. A pharmaceutical composition comprising a pharmaceutically acceptable salt according to claim
 8. 11. A method of treating ischemic arrhythmia, myocardial ischemia and infarction, asthma, chronic vasomotor rhinitis or pain, or a method for gastroprotective therapy, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound according to claim
 1. 